WO2020033377A1 - Histone demethylase 5 inhibitors and uses thereof - Google Patents

Histone demethylase 5 inhibitors and uses thereof Download PDF

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Publication number
WO2020033377A1
WO2020033377A1 PCT/US2019/045259 US2019045259W WO2020033377A1 WO 2020033377 A1 WO2020033377 A1 WO 2020033377A1 US 2019045259 W US2019045259 W US 2019045259W WO 2020033377 A1 WO2020033377 A1 WO 2020033377A1
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certain embodiments
optionally substituted
compound
cancer
pharmaceutically acceptable
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PCT/US2019/045259
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English (en)
French (fr)
Inventor
Jun Qi
Paul M. PARK
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Dana-Farber Cancer Institute, Inc.
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Priority to EP19848392.7A priority Critical patent/EP3833347A4/en
Priority to US17/265,139 priority patent/US20230382865A1/en
Priority to CA3106548A priority patent/CA3106548A1/en
Priority to JP2021505646A priority patent/JP2021534084A/ja
Priority to AU2019318046A priority patent/AU2019318046A1/en
Publication of WO2020033377A1 publication Critical patent/WO2020033377A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C07D213/80—Acids; Esters in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • KDM histone lysine demethylases
  • KDM5A (Lysine demethylase 5A; also known as JARID1A/RBP2) is one of the Jumonji C domain-containing demethylases, which recognizes and removes histone H3 lysine 4 di- and tri-methylation (H3K4me2 and H3K4me3), epigenetic marks of transcriptional gene activation. KDM5A is not only involved in development and differentiation but also involved in
  • KDM5A is highly expressed in multiple myeloma (MM) cell lines and primary MM samples, and higher KDM5A expression is associated with poor prognosis.
  • histone demethylase KDM e.g., KDM5
  • various diseases e.g., cancer
  • modulators of the activity of these histone demethylases including selective modulators (e.g., selective inhibitors) of KDM’s, for use as research tools as well as therapeutic agents in the treatment of various diseases including proliferative diseases such as cancer, and / or cardiovascular disease.
  • Described herein are compounds of Formulae (I) and (II), and salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof.
  • the compounds of Formulae (I) and (II), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, prodrugs, and compositions thereof may inhibit the activity of a histone demethylase in a biological sample or subject.
  • the histone demethylase is KDM5.
  • the compounds of Formulae (I) and (II) are selective for KDM5 compared to other histone demethylases. Also described herein are methods of using the compounds disclosed herein, and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, prodrugs, and compositions thereof, to study the inhibition of a histone demethylase or as therapeutics for the prevention and/or treatment of diseases associated with the overexpression and/or aberrant activity of a histone demethylase.
  • the histone demethylase is KDM5.
  • the aberrant activity is increased activity.
  • the aberrant activity is unwanted activity.
  • the compounds described herein may be useful in treating and/or preventing a disease or condition in a subject. In certain embodiments, the compounds described herein are useful in treating and/or preventing a disease in a subject. In certain embodiments, the disease is a proliferative disease. In certain
  • the disease is cancer. In certain embodiments, the disease is a cardiovascular disease. Also provided are uses, pharmaceutical compositions, and kits including a compound described herein.
  • Exemplary compounds of Formula (I) include, but are not limited to:
  • R 1 , R 1B , R 2 , R 3 , n, and R 7 are as defined herein.
  • Exemplary compounds of Formula (II) include, but are not limited to:
  • the present disclosure provides pharmaceutical compositions including a compound described herein, and optionally a pharmaceutically acceptable excipient.
  • the pharmaceutical compositions described herein include a therapeutically or prophylactically effective amount of a compound described herein.
  • the pharmaceutical composition may be useful for treating and/or preventing a disease in a subject in need thereof, or inhibiting the activity of a histone demethylase in a subject or biological sample.
  • the biological sample is a tissue.
  • the biological sample is a cell.
  • the disease is a proliferative disease.
  • the proliferative disease is cancer.
  • the cancer is lung cancer, breast cancer, liver cancer, pancreatic cancer, gastric cancer, ovarian cancer, colon cancer, or colorectal cancer. In certain embodiments, the cancer is a carcinoma. In certain embodiments, the cancer is multiple myeloma. In certain embodiments, the cardiovascular disease is heart disease. In some embodiments, the heart disease is coronary heart disease.
  • a proliferative disease in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labelled derivative, or prodrug thereof, or a pharmaceutical composition thereof.
  • exemplary proliferative diseases which may be treated include diseases associated with the overexpression or increased activity of a histone demethylase, for example, cancer.
  • the cancer is a carcinoma.
  • the histone demethylase is KDM5.
  • the cancer is selected from the group consisting of lung cancer, breast cancer, liver cancer, pancreatic cancer, gastric cancer, ovarian cancer, colon cancer, and colorectal cancer.
  • the cancer is multiple myeloma.
  • the cancer has a particular genetic mutation.
  • proliferative diseases which may be treated include diseases associated with the overexpression or increased activity of a histone demethylase, for example, cancer.
  • the histone demethylase is KDM5.
  • the cancer is a carcinoma.
  • the cancer is selected from the group consisting of lung cancer, breast cancer, liver cancer, pancreatic cancer, gastric cancer, ovarian cancer, colon cancer, and colorectal cancer.
  • the cancer has a particular genetic mutation.
  • Describe herein are methods for preventing a cardiovascular disease in a subject in need thereof comprising administering to the subject a prophylactically effective amount of a compound described herein, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labelled derivative, or prodrug thereof, or a pharmaceutical composition thereof.
  • Describe herein are methods for treating a cardiovascular disease in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labelled derivative, or prodrug thereof, or a pharmaceutical composition thereof.
  • a histone demethylase in another aspect, described herein are methods of inhibiting a histone demethylase in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labelled derivative, or prodrug thereof, or a pharmaceutical composition thereof.
  • the histone demethylase is KDM5.
  • the method using a compound described herein in a biological sample in some embodiments, the biological sample is a cell. In some embodiments, the biological sample is a tissue.
  • a histone demethylase in another aspect, described herein are methods of inhibiting the activity of a histone demethylase in a biological sample, comprising contacting the biological sample with an effective amount of a compound described herein, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labelled derivative, or prodrug thereof, or a pharmaceutical composition thereof.
  • the histone demethylase is KDM5.
  • Described herein are methods for administering to a subject in need thereof an effective amount of a compound, or pharmaceutical composition thereof, as described herein. Also described are methods for contacting a cell with an effective amount of a compound, or pharmaceutical composition thereof, as described herein. In certain embodiments, a method described herein further includes administering to the subject an additional pharmaceutical agent. In certain embodiments, a method described herein further includes contacting the cell with an additional pharmaceutical agent. In certain embodiments, the additional pharmaceutical agent is an anti-proliferative agent.
  • composition thereof for treating a disease in a subject in need thereof.
  • the present disclosure provides a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer,
  • the present disclosure provides a kit comprising a compound disclosed herein or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labelled derivative, or prodrug thereof, or a pharmaceutical composition thereof, and instructions for administering to a subject or contacting a cell, tissue, or biological sample with the compound, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labelled derivative, or prodrug thereof, or a pharmaceutical composition thereof.
  • kits in a container.
  • the kit includes a single dose or multiple doses of the compound or pharmaceutical composition.
  • the kits may be useful in a method of the disclosure.
  • the kit further includes instructions for using the compound or pharmaceutical composition.
  • a kit described herein may also include information as required by a regulatory agency, such as the U.S. Food and Drug Administration (FDA).
  • the information is prescribing information.
  • Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various isomeric forms, e.g., enantiomers and/or diastereomers.
  • the compounds described herein can be in the form of an individual enantiomer, diastereomer, or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer.
  • Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high
  • HPLC pressure/performance liquid chromatography
  • isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972).
  • the present disclosure additionally encompasses compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.
  • Ci 6 is intended to encompass Ci, C 2 , C 3 , C 4 , Cs, C 6 , Ci 6 , C1 5, Ci ⁇ , C1 3, Ci 2, C 2-6 , C 2-5 , C 2 ⁇ , C 2-3 , C3 6, C3 5, C 3 ⁇ , C4-6, C4-5, and C5 6.
  • Hydrocarbon chain refers to a substituted or unsubstituted divalent alkyl, alkenyl, or alkynyl group.
  • a hydrocarbon chain includes at least one chain, each node (“carbon unit”) of which including at least one carbon atom, between the two radicals of the hydrocarbon chain.
  • hydrocarbon chain -C A H(C B H 2 C c H 3 )- includes only one carbon unit C A .
  • C x hydrocarbon chain refers to a hydrocarbon chain that includes x number of carbon unit(s) between the two radicals of the hydrocarbon chain. If there is more than one possible value of x, the smallest possible value of x is used for the definition of the hydrocarbon chain.
  • -CH(C 2 Hs)- is a Ci hydrocarbon chain
  • a hydrocarbon chain may be saturated (e.g., -(CH 2 ) 4- ) ⁇
  • the hydrocarbon chain is unsubstituted (e.g.,— (CH 2 ) 4— ) .
  • the hydrocarbon chain is substituted (e.g., -CH(C 2 Hs)- and -CF 2- ). Any two substituents on the hydrocarbon chain may be joined to form an optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or
  • Alkyl refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 20 carbon atoms (“Ci 2 o alkyl”). In some embodiments, an alkyl group has 1 to
  • an alkyl group has 1 to 9 carbon atoms (“Ci 9 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C i x alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“Ci 7 alkyl”). In some
  • an alkyl group has 1 to 6 carbon atoms (“Ci 6 alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C1 5 alkyl”). In some embodiments, an alkyl group has 1 to
  • Ci 6 alkyl groups include, but are not limited to, methyl (Ci), ethyl (C 2 ), «-propyl (C 3 ), isopropyl (C 3 ), «-butyl (C 4 ), / ⁇ ?
  • each instance of an alkyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkyl”) or substituted (a“substituted alkyl”) with one or more substituents.
  • the alkyl group is unsubstituted Ci-io alkyl (e.g., -CH 3 ).
  • the alkyl group is substituted Ci-io alkyl.
  • alkenyl refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon-carbon double bonds, and no triple bonds (“C2-20 alkenyl”).
  • an alkenyl group has 2 to 10 carbon atoms (“C2-10 alkenyl”).
  • an alkenyl group has 2 to 9 carbon atoms (“C2-9 alkenyl”).
  • an alkenyl group has 2 to 8 carbon atoms (“C2-8 alkenyl”).
  • an alkenyl group has 2 to 7 carbon atoms (“C2-7 alkenyl”).
  • an alkenyl group has 2 to 6 carbon atoms (“C2-6 alkenyl”). In some embodiments, an alkenyl group has 2 to 5 carbon atoms (“C2-5 alkenyl”). In some embodiments, an alkenyl group has 2 to 4 carbon atoms (“C2 ⁇ alkenyl”). In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C2-3 alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C2 alkenyl”). The one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in l-butenyl).
  • Examples of C2-4 alkenyl groups include ethenyl (C2), l-propenyl (C 3 ), 2-propenyl (C 3 ), l-butenyl (C 4 ), 2-butenyl (C 4 ), butadienyl (C 4 ), and the like.
  • Examples of C2-6 alkenyl groups include the aforementioned C2-4 alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (C 6 ), and the like. Additional examples of alkenyl include heptenyl (C 7 ), octenyl (Cs), octatrienyl (Cs), and the like.
  • each instance of an alkenyl group is independently optionally substituted, i.e., unsubstituted (an“unsubstituted alkenyl”) or substituted (a“substituted alkenyl”) with one or more substituents.
  • the alkenyl group is unsubstituted C2-10 alkenyl.
  • the alkenyl group is substituted C2-10 alkenyl.
  • Alkynyl refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon-carbon triple bonds, and optionally one or more double bonds (“C2-20 alkynyl”).
  • an alkynyl group has 2 to 10 carbon atoms (“C2-10 alkynyl”).
  • an alkynyl group has 2 to 9 carbon atoms (“C2-9 alkynyl”).
  • an alkynyl group has 2 to 8 carbon atoms (“C2-8 alkynyl”).
  • an alkynyl group has 2 to 7 carbon atoms (“C2-7 alkynyl”).
  • an alkynyl group has 2 to 6 carbon atoms (“C2-6 alkynyl”). In some embodiments, an alkynyl group has 2 to 5 carbon atoms (“C2-5 alkynyl”). In some embodiments, an alkynyl group has 2 to 4 carbon atoms (“C2-4 alkynyl”). In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C2 3 alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms (“C 2 alkynyl”). The one or more carbon-carbon triple bonds can be internal (such as in 2- butynyl) or terminal (such as in l-butynyl).
  • C 2 ⁇ alkynyl groups include, without limitation, ethynyl (C 2 ), l-propynyl (C 3 ), 2-propynyl (C 3 ), l-butynyl (C 4 ), 2-butynyl (C 4 ), and the like.
  • Examples of C 2-6 alkenyl groups include the aforementioned C 2 4 alkynyl groups as well as pentynyl (C 5 ), hexynyl (Co), and the like.
  • Additional examples of alkynyl include heptynyl (C 7 ), octynyl (Cs), and the like.
  • each instance of an alkynyl group is independently optionally substituted, i.e., unsubstituted (an“unsubstituted alkynyl”) or substituted (a“substituted alkynyl”) with one or more substituents.
  • the alkynyl group is unsubstituted C 2-i o alkynyl.
  • the alkynyl group is substituted C 2-i o alkynyl.
  • Carbocyclyl or“carbocyclic” refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 10 ring carbon atoms (“C 3-i o carbocyclyl”) in the non-aromatic ring system.
  • a carbocyclyl group has 3 to 8 ring carbon atoms (“C 3-g carbocyclyl”).
  • a carbocyclyl group has 3 to 6 ring carbon atoms (“C 3-6 carbocyclyl”).
  • a carbocyclyl group has 3 to 6 ring carbon atoms (“C 3-6 carbocyclyl”).
  • a carbocyclyl group has 5 to 10 ring carbon atoms (“C5 10 carbocyclyl”).
  • C5 10 carbocyclyl ring carbon atoms
  • Exemplary C 3-6 carbocyclyl groups include, without limitation, cyclopropyl (C 3 ), cyclopropenyl (C 3 ), cyclobutyl (C 4 ), cyclobutenyl (C 4 ), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (Co), cyclohexenyl (Co), cyclohexadienyl (Co), and the like.
  • Exemplary C 3 s carbocyclyl groups include, without limitation, the aforementioned C 3-6 carbocyclyl groups as well as cycloheptyl (C 7 ), cycloheptenyl (C 7 ), cycloheptadienyl (C 7 ), cycloheptatrienyl (C 7 ), cyclooctyl (Cs), cyclooctenyl (Cs), bicyclo[2.2.l]heptanyl (C 7 ), bicyclo[2.2.2]octanyl (Cs), and the like.
  • Exemplary C 3-i o carbocyclyl groups include, without limitation, the aforementioned C 3 s carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1 /7-indcnyl (C9), decahydronaphthalenyl (C10), spiro[4.5]decanyl (C10), and the like.
  • the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or contain a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) and can be saturated or can be partially unsaturated.
  • “Carbocyclyl” also includes ring systems wherein the carbocyclic ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclic ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system.
  • each instance of a carbocyclyl group is independently optionally substituted, i.e., unsubstituted (an“unsubstituted carbocyclyl”) or substituted (a“substituted carbocyclyl”) with one or more substituents.
  • the carbocyclyl group is unsubstituted C 3-10 carbocyclyl.
  • the carbocyclyl group is a substituted C 3-10 carbocyclyl.
  • “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 10 ring carbon atoms (“C 3-10 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms (“C 3-8 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C 3-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C 5-6 cycloalkyl”).
  • a cycloalkyl group has 5 to 10 ring carbon atoms (“C 5-10 cycloalkyl”).
  • C 5-6 cycloalkyl groups include cyclopentyl (C 5 ) and cyclohexyl (Co).
  • C 3-6 cycloalkyl groups include the aforementioned C 5-6 cycloalkyl groups as well as cyclopropyl (C 3 ) and cyclobutyl (C 4 ).
  • Non limiting examples of C 3-8 cycloalkyl groups include the aforementioned C 3-6 cycloalkyl groups as well as cycloheptyl (C 7 ) and cyclooctyl (Cs).
  • each instance of a cycloalkyl group is independently unsubstituted (an“unsubstituted cycloalkyl”) or substituted (a “substituted cycloalkyl”) with one or more substituents.
  • the cycloalkyl group is unsubstituted C 3-10 cycloalkyl.
  • the cycloalkyl group is substituted C 3-10 cycloalkyl.
  • “Heterocyclyl” or“heterocyclic” refers to a radical of a 3- to lO-membered non aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from the group consisting of nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (i.e., a“3-10 membered heterocyclyl”).
  • the point of attachment can be a carbon or nitrogen atom, as valency permits.
  • a heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”), and can be saturated or can be partially unsaturated.
  • Heterocyclyl bicyclic ring systems can include one or more heteroatoms in one or both rings.“Heterocyclyl” also includes ring systems wherein the heterocyclic ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclic ring, or ring systems wherein the heterocyclic ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclic ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclic ring system. Unless otherwise specified, each instance of heterocyclyl is
  • heterocyclyl group is unsubstituted 3-10 membered heterocyclyl. In certain embodiments, the heterocyclyl group is substituted 3-10 membered heterocyclyl.
  • a heterocyclyl group is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from the group consisting of nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5-10 membered heterocyclyl”).
  • a heterocyclyl group is a 5- 8 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from the group consisting of nitrogen, oxygen, boron, silicon, phosphorous, and sulfur (“5-8 membered heterocyclyl”).
  • a heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from the group consisting of nitrogen, oxygen, boron, silicon, phosphorous, and sulfur (“5-6 membered heterocyclyl”).
  • the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5-6 membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur.
  • Exemplary 3-membered heterocyclyl groups containing one heteroatom include, without limitation, aziridinyl, oxiranyl, and thiiranyl.
  • Exemplary 4-membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl.
  • Exemplary 5-membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione.
  • Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one.
  • Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl.
  • Exemplary 6-membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl.
  • Exemplary 6- membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, and dioxanyl.
  • Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, triazinanyl.
  • Exemplary 7-membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl.
  • Exemplary 8-membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl.
  • Exemplary 5-membered heterocyclyl groups fused to a C 6 aryl ring include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like.
  • Exemplary 6-membered heterocyclyl groups fused to an aryl ring include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.
  • Aryl refers to a radical of a monocyclic or polycyclic (e.g ., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C6-14 aryl”).
  • an aryl group has six ring carbon atoms (“C 6 aryl”; e.g., phenyl).
  • an aryl group has ten ring carbon atoms (“Cio aryl”; e.g., naphthyl such as 1- naphthyl and 2-naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms (“Ci4 aryl”; e.g., anthracyl).“Aryl” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system.
  • each instance of an aryl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted aryl”) or substituted (a“substituted aryl”) with one or more substituents.
  • the aryl group is unsubstituted C6-14 aryl.
  • the aryl group is substituted C6-14 aryl.
  • “Aralkyl” is a subset of alkyl and aryl and refers to an optionally substituted alkyl group substituted by an optionally substituted aryl group.
  • the aralkyl is optionally substituted benzyl.
  • the aralkyl is benzyl.
  • the aralkyl is optionally substituted phenethyl.
  • the aralkyl is phenethyl.
  • Heteroaryl refers to a radical of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system ( e.g ., having 6 or 10 pi electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from the group consisting of nitrogen, oxygen and sulfur (“5-10 membered heteroaryl”).
  • the point of attachment can be a carbon or nitrogen atom, as valency permits.
  • Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings.
  • “Heteroaryl” includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system.
  • “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused (aryl/heteroaryl) ring system.
  • Bicyclic heteroaryl groups wherein one ring does not contain a heteroatom e.g., indolyl, quinolinyl, carbazolyl, and the like
  • the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl).
  • a heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from the group consisting of nitrogen, oxygen, and sulfur.
  • a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from the group consisting of nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”).
  • a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from the group consisting of nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”).
  • the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.
  • each instance of a heteroaryl group is independently optionally substituted, i.e., unsubstituted (an“unsubstituted heteroaryl”) or substituted (a“substituted heteroaryl”) with one or more substituents.
  • the heteroaryl group is unsubstituted 5-14 membered heteroaryl. In certain embodiments, the heteroaryl group is substituted 5-14 membered heteroaryl.
  • Exemplary 5-membered heteroaryl groups containing one heteroatom include, without limitation, pyrrolyl, furanyl and thiophenyl.
  • Exemplary 5-membered heteroaryl groups containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl.
  • Exemplary 5-membered heteroaryl groups containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl.
  • Exemplary 5-membered heteroaryl groups containing four heteroatoms include, without limitation, tetrazolyl.
  • Exemplary 6-membered heteroaryl groups containing one heteroatom include, without limitation, pyridinyl.
  • Exemplary 6-membered heteroaryl groups containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl.
  • Exemplary 6- membered heteroaryl groups containing three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively.
  • Exemplary 7-membered heteroaryl groups containing one heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl.
  • Exemplary 5,6- bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl,
  • benzotriazolyl benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl.
  • Exemplary 6,6-bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.
  • Hetero aralkyl is a subset of alkyl and heteroaryl and refers to an optionally substituted alkyl group substituted by an optionally substituted heteroaryl group.
  • Partially unsaturated refers to a group that includes at least one double or triple bond.
  • a “partially unsaturated” ring system is further intended to encompass rings having multiple sites of unsaturation but is not intended to include aromatic groups (e.g aryl or heteroaryl groups) as defined herein.
  • “saturated” refers to a group that does not contain a double or triple bond, i.e., contains all single bonds.
  • Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups, which are divalent bridging groups are optionally further referred to using the suffix -ene, e.g., alkylene, alkenylene, alkynylene, carbocyclylene, heterocyclylene, arylene, and heteroarylene.
  • optionally substituted refers to substituted with one or more optional substituents or unsubstituted.
  • Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted (e.g.,“substituted” or“unsubstituted” alkyl,“substituted” or
  • substituted carbocyclyl,“substituted” or“unsubstituted” heterocyclyl,“substituted” or “unsubstituted” aryl or“substituted” or“unsubstituted” heteroaryl group).
  • substituted whether preceded by the term“optionally” or not, means that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction.
  • a“substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position.
  • the term“substituted” is contemplated to include substitution with all permissible substituents of organic compounds, any of the substituents described herein that results in the formation of a stable compound.
  • the present disclosure contemplates any and all such combinations in order to arrive at a stable compound.
  • heteroatoms such as nitrogen may have hydrogen substituents and/or any suitable substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety.
  • Ci-io alkyl CHO perhaloalkyl, C 2-i o alkenyl, C 2-i o alkynyl, heteroCi-io alkyl, heteroC 2-i o alkenyl, heteroC 2-i o alkynyl, C 3-i o carbocyclyl, 3-14 membered heterocyclyl, C 6-i 4 aryl, and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, hetero
  • R ⁇ is, independently, selected from CHO alkyl, Ci-io perhaloalkyl, C 2-i o alkenyl, C 2-i o alkynyl, heteroCi-io alkyl, heteroC 2-i oalkenyl, heteroC 2-i oalkynyl, C 3-i o carbocyclyl, 3-14 membered heterocyclyl, C 6-i 4 aryl, and 5-14 membered heteroaryl, or two R aa groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalky
  • each instance of R cc is, independently, selected from hydrogen, Ci-io alkyl, Ci-io perhaloalkyl, C 2-i o alkenyl, C 2-i o alkynyl, heteroCi-io alkyl, heteroC 2-i o alkenyl, heteroC 2-i o alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C 6-i 4 aryl, and 5-14 membered heteroaryl, or two R cc groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups;
  • each instance of R ee is, independently, selected from Ci -6 alkyl, Ci -6 perhaloalkyl, C2-6 alkenyl, C2-6 alkynyl, heteroCi-6 alkyl, heteroC2-6alkenyl, heteroC 2-6 alkynyl, C3-10 carbocyclyl, C6-10 aryl, 3-10 membered heterocyclyl, and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups;
  • each instance of R ff is, independently, selected from hydrogen, Ci -6 alkyl, Ci -6
  • A“counterion” or“anionic counterion” is a negatively charged group associated with a positively charged group in order to maintain electronic neutrality.
  • An anionic counterion may be monovalent (i.e., including one formal negative charge).
  • An anionic counterion may also be multivalent (i.e., including more than one formal negative charge), such as divalent or trivalent.
  • Exemplary counterions include halide ions (e.g ., F , Cl-, Br , G), N0 3 , C10 4 , OH-, H 2 P0 4 , HC0 3 , HSO4 , sulfonate ions (e.g., methansulfonate, trifluoromethanesulfonate, p- toluenesulfonate, benzenesulfonate, 10-camphor sulfonate, naphthalene-2-sulfonate, naphthalene- 1 -sulfonic acid-5-sulfonate, ethan-l -sulfonic acid-2-sulfonate, and the like), carboxylate ions (e.g., acetate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, gluconate, and the like), BF 4 , PF 4 -, PF 6 , As
  • Exemplary counterions which may be multivalent include C0 3 2- , HP0 4 2- , P0 4 3- , B 4 0 7 2- , S0 4 2- , S 2 0 3 2- , carboxylate anions (e.g., tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalates, aspartate, glutamate, and the like), and carboranes.
  • carboxylate anions e.g., tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalates, aspartate, glutamate, and the like
  • carboranes e.g., tartrate, citrate, fumarate, maleate, malate
  • Halo or“halogen” refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), or iodine (iodo, -I).
  • acyl groups include aldehydes (-CHO), carboxylic acids (-C0 2 H), ketones, acyl halides, esters, amides, imines, carbonates, carbamates, and ureas.
  • Acyl substituents include, but are not limited to, any of the substituents described herein, that result in the formation of a stable moiety (e.g., aliphatic, alkyl, alkenyl, alkynyl, heteroaliphatic, heterocyclic, aryl, heteroaryl, acyl, oxo, imino, thiooxo, cyano, isocyano, amino, azido, nitro, hydroxyl, thiol, halo, aliphaticamino, heteroaliphaticamino, alkylamino, heteroalkylamino, arylamino, heteroarylamino, alkylaryl, arylalkyl, aliphaticoxy, heteroaliphaticoxy, alky
  • “Alkoxy” or“alkoxyl” refers to a radical of the formula: -O-alkyl.
  • Nitrogen atoms can be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quaternary nitrogen atoms.
  • the substituent present on a nitrogen atom is a nitrogen protecting group (also referred to as an amino protecting group).
  • Nitrogen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis , T. W. Greene and P. G. M. Wuts, 3 rd edition, John Wiley & Sons, 1999, incorporated herein by reference.
  • Nitrogen protecting groups such as carbamate groups include, but are not limited to, methyl carbamate, ethyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), 9-(2- sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluoroenylmethyl carbamate, 2,7— di—/— butyl— [9-(l0,l0-dioxo-l0,l0,l0,l0-tetrahydrothioxanthyl)]methyl carbamate (DBD-Tmoc), 4- methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2- trimethylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), l-(l-adamantyl
  • Nitrogen protecting groups such as sulfonamide groups include, but are not limited to, p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6,-trimethyl-4- methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl- 4-methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide (Mts), 2,6- dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6- sulfonamide (Pmc), methan
  • nitrogen protecting groups include, but are not limited to, phenothiazinyl-(lO)-acyl derivative, A'-/;-t o 1 u c n c s u 1 fo n y 1 a m i n o acyl derivative, A'-p h c n y 1 a m i n o t h i o ac y 1 derivative, A- benzoylphenylalanyl derivative, A-acct y 1 met h i o nine derivative, 4,5-diphenyl-3-oxazolin-2- one, A-phthalimidc, /V-dithiasuccinimide (Dts), A-2,3-diphenylmaleimide, N- 2,5- dimethylpyrrole, A-l , 1 4-tctramcthyldisilyla/acyclopcntanc adduct (STABASE), 5- substitute
  • diphenylphosphinamide Dpp
  • dimethylthiophosphinamide Mpt
  • diphenylthiophosphinamide Ppt
  • dialkyl phosphoramidates dibenzyl phosphoramidate, diphenyl phosphoramidate
  • benzenesulfenamide o-nitrobenzenesulfenamide (Nps)
  • 2,4-dinitrobenzenesulfenamide pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide
  • triphenylmethylsulfenamide triphenylmethylsulfenamide
  • 3-nitropyridinesulfenamide Npys
  • the substituent present on an oxygen atom is an oxygen protecting group (also referred to herein as an“hydroxyl protecting group”).
  • Oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3 rd edition, John Wiley & Sons, 1999, incorporated herein by reference.
  • oxygen protecting groups include, but are not limited to, methyl,
  • MOM methoxylmethyl
  • MTM methylthiomethyl
  • bromophenacyloxyphenyl)diphenylmethyl 4,4',4"-tris(4,5-dichlorophthalimidophenyl)methyl, 4,4',4"-tris(levulinoyloxyphenyl)methyl, 4,4',4"-tris(benzoyloxyphenyl)methyl, 3-(imidazol-l- yl)bis(4',4"-dimethoxyphenyl)methyl, l,l-bis(4-methoxyphenyl)-l '-pyrenylmethyl, 9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-l0-oxo)anthryl, 1 ,3-benzodisulfuran-2-yl,
  • benzisothiazolyl S,S-dioxido trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethylthexylsilyl, t- butyldimethylsilyl (TBDMS), /-butyldiphenylsilyl (TBDPS), tribenzylsilyl, t ri— /?— x y 1 y 1 s i 1 y 1 , triphenylsilyl, diphenylmethylsilyl (DPMS), /-butylmethoxyphenylsilyl (TBMPS), formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxy
  • the substituent present on a sulfur atom is a sulfur protecting group (also referred to as a“thiol protecting group”).
  • Sulfur protecting groups include, but are not limited to,
  • Sulfur protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3 rd edition, John Wiley & Sons, 1999, incorporated herein by reference.
  • a“leaving group” is an art-understood term referring to a molecular fragment that departs with a pair of electrons in a heterolytic bond cleavage, wherein the molecular fragment is an anion or neutral molecule.
  • a leaving group can be an atom or a group capable of being displaced by a nucleophile. See, for example, Smith, March Advanced Organic Chemistry 6th ed. (501-502).
  • alkanesulfonyloxy arenesulfonyloxy, alkyl-carbonyloxy (e.g., acetoxy), arylcarbonyloxy, aryloxy, methoxy, /V,(9-dimethylhydroxylamino, pixyl, and haloformates.
  • the leaving group is a sulfonic acid ester, such as toluenesulfonate (tosylate, -OTs),
  • the leaving group is a brosylate, such as p-bromobenzenesulfonyloxy.
  • the leaving group is a nosylate, such as 2- nitrobenzenesulfonyloxy.
  • the leaving group is a sulfonate-containing group. In some embodiments, the leaving group is a tosylate group.
  • the leaving group may also be a phosphineoxide (e.g ., formed during a Mitsunobu reaction) or an internal leaving group such as an epoxide or cyclic sulfate.
  • phosphineoxide e.g ., formed during a Mitsunobu reaction
  • an internal leaving group such as an epoxide or cyclic sulfate.
  • Other non-limiting examples of leaving groups are water, amines, ammonia, alcohols, ether moieties, sulfur-containing moieties, thioether moieties, zinc halides, magnesium moieties, diazonium salts, and copper moieties.
  • pharmaceutically acceptable salt refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, Berge et al, describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference.
  • Pharmaceutically acceptable salts of the compounds of the present disclosure include those derived from suitable inorganic and organic acids and bases.
  • suitable inorganic and organic acids and bases include those derived from suitable inorganic and organic acids and bases.
  • pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate,
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (Ci 4 alkyl) 4 salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.
  • solvate refers to forms of the compound that are associated with a solvent, usually by a solvolysis reaction. This physical association may include hydrogen bonding.
  • solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like.
  • the compounds of Formulae (I) or (II) may be prepared, e.g., in crystalline form, and may be solvated.
  • Suitable solvates include pharmaceutically acceptable solvates and further include both stoichiometric solvates and non- stoichiometric solvates.
  • the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated in the crystal lattice of a crystalline solid.“Solvate” encompasses both solution- phase and isolable solvates.
  • Representative solvates include hydrates, ethanolates, and methanolates.
  • hydrate refers to a compound that is associated with water.
  • the number of the water molecules contained in a hydrate of a compound is in a definite ratio to the number of the compound molecules in the hydrate. Therefore, a hydrate of a compound may be represented, for example, by the general formula R x H 2 0, wherein R is the compound and wherein x is a number greater than 0.
  • a given compound may form more than one type of hydrates, including, e.g., monohydrates (x is 1), lower hydrates (x is a number greater than 0 and smaller than 1, e.g., hemihydrates (R-0.5 H 2 0)), and polyhydrates (x is a number greater than 1, e.g., dihydrates (R-2 H 2 0) and hexahydrates (R-6 H 2 0)).
  • monohydrates x is 1
  • lower hydrates x is a number greater than 0 and smaller than 1, e.g., hemihydrates (R-0.5 H 2 0)
  • polyhydrates x is a number greater than 1, e.g., dihydrates (R-2 H 2 0) and hexahydrates (R-6 H 2 0)
  • tautomers refer to compounds that are interchangeable forms of a particular compound structure, and that vary in the displacement of hydrogen atoms and electrons. Thus, two structures may be in equilibrium through the movement of p electrons and an atom (usually H). For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base. Another example of tautomerism is the aci- and nitro- forms of phenylnitromethane, that are likewise formed by treatment with acid or base.
  • Tautomeric forms may be relevant to the attainment of the optimal chemical reactivity and biological activity of a compound of interest.
  • An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory ( i.e ., as (+) or (-)-isomers respectively).
  • a chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a“racemic mixture.”
  • polymorphs refers to a crystalline form of a compound (or a salt, hydrate, or solvate thereof) in a particular crystal packing arrangement. All polymorphs have the same elemental composition. Different crystalline forms usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. Recrystallization solvent, rate of crystallization, storage temperature, and other factors may cause one crystal form to dominate. Various polymorphs of a compound can be prepared by crystallization under different conditions.
  • co-crystal refers to a crystalline structure comprising at least two different components (e.g ., a compound of Formula (I) and an acid), wherein each of the components is independently an atom, ion, or molecule. In certain embodiments, none of the components are a solvent. In certain embodiments, at least one of the components is a solvent.
  • a co-crystal of a compound of Formula (I) and an acid is different from a salt formed from a compound of Formula (I) and an acid.
  • a compound of Formula (I) is complexed with the acid in a way that proton transfer (e.g., a complete proton transfer) from the acid to a compound of Formula (I) easily occurs at room temperature.
  • a compound of Formula (I) is complexed with the acid in a way that proton transfer from the acid to a compound Formula (I) does not easily occur at room temperature.
  • Co-crystals may be useful to improve the properties (e.g., solubility, stability, and ease of formulation) of a compound of Formula (I).
  • structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, replacement of 19 F with 18 F, or the replacement of 12 C with 13 C or 14 C are within the scope of the disclosure.
  • Such isotopically labeled derivatives are useful, for example, as analytical tools or probes in biological assays.
  • prodrugs refer to compounds, including derivatives of the compounds of Formulae (I) or (II), which have cleavable groups and become by solvolysis or under
  • the compounds of Formulae (I) or (II) which are pharmaceutically active in vivo include, but are not limited to, ester derivatives and the like.
  • Other derivatives of the compounds of this disclosure have activity in both their acid and acid derivative forms, but in the acid sensitive form often offers advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (see, Bundgard, H., Design of Prodrugs , pp. 7-9, 21-24, Elsevier, Amsterdam 1985).
  • Prodrugs include acid derivatives well known to practitioners of the art, such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides.
  • Simple aliphatic or aromatic esters, amides, and anhydrides derived from acidic groups pendant on the compounds of this disclosure are particular prodrugs.
  • double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters.
  • the compound is a Ci-C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, aryl, C 7 -Ci 2 substituted aryl, or C 7 -Ci 2 arylalkyl ester prodrug.
  • the prodrug is a Ci- Cs alkyl ester.
  • the prodrug is a C 2 -C 8 alkenyl ester.
  • the prodrug is a C 2 -C 8 alkynyl ester. In certain embodiments, the prodrug is an aryl ester. In certain embodiments, the prodrug is a C 7 -Ci 2 substituted aryl ester. In certain embodiments, the prodrug is a C 7 -Ci 2 arylalkyl ester.
  • A“subject” to which administration is contemplated includes, but is not limited to, humans (i.e ., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult, or senior adult)) and/or other non-human animals, for example, mammals (e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys); commercially relevant mammals such as cattle, pigs, horses, sheep, goats, cats, and/or dogs) and birds ( e.g ., commercially relevant birds such as chickens, ducks, geese, and/or turkeys).
  • the animal is a mammal.
  • the animal may be a male or female and at any stage of development.
  • a non-human animal may be a transgenic animal.
  • administer refers to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound according to the present disclosure, or a pharmaceutical composition thereof.
  • treatment refers to reversing, alleviating, delaying the onset of, or inhibiting the progress of a“pathological condition” (e.g., a disease, disorder, or condition, or one or more signs or symptoms thereof) described herein.
  • a“pathological condition” e.g., a disease, disorder, or condition, or one or more signs or symptoms thereof
  • treatment may be administered after one or more signs or symptoms have developed or have been observed.
  • treatment may be administered in the absence of signs or symptoms of the disease or condition.
  • treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence.
  • “treatment,”“treat,” and“treating” refer to reversing the progress of a pathological condition. In some embodiments,“treatment,”“treat,” and“treating” refer to reversing the progress of one or more symptoms of a pathological condition.
  • “treatment,”“treat,” and“treating” refer to alleviating a pathological condition. In some embodiments,“treatment,”“treat,” and“treating” refer to alleviating one or more symptoms of a pathological condition.
  • “treatment,”“treat,” and“treating” refer to delaying the onset of a pathological condition. In some embodiments,“treatment,”“treat,” and“treating” refer to delaying the onset of one or more symptoms of a pathological condition.
  • “treatment,”“treat,” and“treating” refer to inhibiting the progress of a pathological condition. In some embodiments,“treatment,”“treat,” and“treating” refer to inhibiting the progress of one or more symptoms of a pathological condition.
  • an“effective amount” of a compound of Formulae (I) or (II) refers to an amount sufficient to elicit the desired biological response, i.e., treating the condition.
  • the effective amount of a compound of Formulae (I) or (II) may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the condition being treated, the mode of administration, and the age and health of the subject.
  • An effective amount encompasses therapeutic and prophylactic treatment.
  • an effective amount of a compound disclosed herein may reduce the tumor burden or stop the growth or spread of a tumor.
  • A“therapeutically effective amount” of a compound of Formulae (I) or (II) is an amount sufficient to provide a therapeutic benefit in the treatment of a condition or to delay or minimize one or more symptoms associated with the condition.
  • a therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the condition.
  • the term“therapeutically effective amount” can encompass an amount that improves overall therapy, reduces, or avoids symptoms or causes of the condition, or enhances the therapeutic efficacy of another therapeutic agent.
  • A“prophylactically effective amount” of a compound of Formulae (I) or (II) is an amount sufficient to prevent a condition, or one or more symptoms associated with the condition or prevent its recurrence.
  • a prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of the condition.
  • the term“prophylactically effective amount” can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.
  • the prophylactically effective amount improves overall prophylaxis.
  • the period of prophylaxis is the life of the subject.
  • the period of prophylaxis is greater than or equal to 50 years. In some embodiments, the period of prophylaxis is greater than or equal to 40 years. In some embodiments, the period of prophylaxis is greater than or equal to 30 years. In some
  • the period of prophylaxis is greater than or equal to 20 years. In some embodiments, the period of prophylaxis is greater than or equal to 20 years. In some embodiments, the period of prophylaxis is greater than or equal to 20 years. In some embodiments, the period of prophylaxis is greater than or equal to 20 years. In some embodiments, the period of prophylaxis is greater than or equal to 20 years. In some embodiments, the period of prophylaxis is greater than or equal to 20 years. In some combination
  • the period of prophylaxis is greater than or equal to 10 years. In some embodiments, the period of prophylaxis is greater than or equal to 10 years. In some embodiments, the period of prophylaxis is greater than or equal to 10 years. In some embodiments, the period of prophylaxis is greater than or equal to 10 years. In some embodiments, the period of prophylaxis is greater than or equal to 10 years.
  • the period of prophylaxis is greater than or equal to 5 years. In some embodiments, the period of prophylaxis is greater than or equal to 5 years. In some embodiments, the period of prophylaxis is greater than or equal to 5 years. In some embodiments, the period of prophylaxis is greater than or equal to 5 years. In some embodiments, the period of prophylaxis is greater than or equal to 5 years.
  • the period of prophylaxis is greater than or equal to 4 years. In some embodiments, the period of prophylaxis is greater than or equal to 4 years. In some embodiments, the period of prophylaxis is greater than or equal to 4 years. In some embodiments, the period of prophylaxis is greater than or equal to 4 years. In some embodiments, the period of prophylaxis is greater than or equal to 4 years.
  • the period of prophylaxis is 3 greater than or equal to years. In some embodiments, the period of prophylaxis is 3 greater than or equal to years. In some
  • the period of prophylaxis is greater than or equal to 2 years. In some embodiments, the period of prophylaxis is greater than or equal to 2 years. In some embodiments, the period of prophylaxis is greater than or equal to 2 years. In some embodiments, the period of prophylaxis is greater than or equal to 2 years. In some embodiments, the period of prophylaxis is greater than or equal to 2 years.
  • the period of prophylaxis is greater than or equal to 1 year. In some embodiments, the period of prophylaxis is greater than or equal to 11 months. In some embodiments, the period of prophylaxis is greater than or equal to 10 months. In some embodiments, the period of prophylaxis is greater than or equal to 9 months. In some embodiments, the period of prophylaxis is greater than or equal to 8 months. In some embodiments, the period of prophylaxis is greater than or equal to 7 months. In some embodiments, the period of prophylaxis is greater than or equal to 6 months. In some embodiments, the period of prophylaxis is greater than or equal to 5 months.
  • the period of prophylaxis is greater than or equal to 4 months. In some embodiments, the period of prophylaxis is greater than or equal to 3 months. In some embodiments, the period of prophylaxis is greater than or equal to 2 months. In some embodiments, the period of prophylaxis is greater than or equal to 1 month.
  • A“proliferative disease” refers to a disease that occurs due to abnormal growth or extension by the multiplication of cells (Walker, Cambridge Dictionary of Biology, Cambridge University Press: Cambridge, UK, 1990).
  • a proliferative disease may be associated with: 1) the pathological proliferation of normally quiescent cells; 2) the pathological migration of cells from their normal location ( e.g ., metastasis of neoplastic cells); 3) the pathological expression of proteolytic enzymes such as the matrix metalloproteinases (e.g., collagenases, gelatinases, and elastases); or 4) the pathological angiogenesis as in proliferative retinopathy and tumor metastasis.
  • Exemplary proliferative diseases include cancers ( i.e .,“malignant neoplasms”), benign neoplasms, angiogenesis, inflammatory diseases, autoinflammatory diseases, and autoimmune diseases.
  • neoplasm and“tumor” are used interchangeably and refer to an abnormal mass of tissue wherein the growth of the mass surpasses and is not coordinated with the growth of a normal tissue.
  • a neoplasm or tumor may be“benign” or“malignant,” depending on the following characteristics: degree of cellular differentiation (including morphology and functionality), rate of growth, local invasion, and metastasis.
  • A“benign neoplasm” is generally well differentiated, has characteristically slower growth than a malignant neoplasm, and remains localized to the site of origin.
  • a benign neoplasm does not have the capacity to infiltrate, invade, or metastasize to distant sites.
  • Exemplary benign neoplasms include, but are not limited to, lipoma, chondroma, adenomas, acrochordon, senile angiomas, seborrheic keratoses, lentigos, and sebaceous hyperplasias.
  • certain“benign” tumors may later give rise to malignant neoplasms, which may result from additional genetic changes in a subpopulation of the tumor’s neoplastic cells, and these tumors are referred to as“pre-malignant neoplasms.”
  • An exemplary pre-malignant neoplasm is a teratoma.
  • a“malignant neoplasm” is generally poorly differentiated (anaplasia) and has characteristically rapid growth accompanied by progressive infiltration, invasion, and destruction of the surrounding tissue. Furthermore, a malignant neoplasm generally has the capacity to metastasize to distant sites.
  • the term“metastasis,”“metastatic,” or“metastasize” refers to the spread or migration of cancerous cells from a primary or original tumor to another organ or tissue and is typically identifiable by the presence of a“secondary tumor” or“secondary cell mass” of the tissue type of the primary or original tumor and not of that of the organ or tissue in which the secondary (metastatic) tumor is located.
  • a prostate cancer that has migrated to bone is said to be metastasized prostate cancer and includes cancerous prostate cancer cells growing in bone tissue.
  • cancer refers to a malignant neoplasm ( Stedman’s Medical Dictionary , 25th ed.; Hensyl ed.; Williams & Wilkins: Philadelphia, 1990).
  • exemplary cancers include, but are not limited to, acoustic neuroma; adenocarcinoma; adrenal gland cancer; anal cancer;
  • angiosarcoma e.g ., lymphangio sarcoma, lymphangioendotheliosarcoma, hemangiosarcoma
  • appendix cancer benign monoclonal gammopathy
  • biliary cancer e.g., cholangiocarcinoma
  • bladder cancer breast cancer (e.g., adenocarcinoma of the breast, papillary carcinoma of the breast, mammary cancer, medullary carcinoma of the breast); brain cancer (e.g., meningioma, glioblastomas, glioma (e.g., astrocytoma, oligodendroglioma), medulloblastoma); bronchus cancer; carcinoid tumor; cervical cancer (e.g., cervical adenocarcinoma); choriocarcinoma;
  • cervical cancer e.g., cervical adenocarcinoma
  • choriocarcinoma e
  • chordoma a chordoma
  • craniopharyngioma a colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma); connective tissue cancer; epithelial carcinoma; ependymoma;
  • endotheliosarcoma e.g., Kaposi’s sarcoma, multiple idiopathic hemorrhagic sarcoma
  • endometrial cancer e.g., uterine cancer, uterine sarcoma
  • esophageal cancer e.g.,
  • lymphoma such as Hodgkin lymphoma (HL) (e.g., B-cell HL, T-cell HL) and non-Hodgkin lymphoma (NHL) (e.g., B-cell NHL such as diffuse large cell lymphoma (DLCL) (e.g., diffuse large B-cell lymphoma), follicular lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphomas (e.g., mucosa-associated lymphoid tissue (MALT) lymphomas, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma (i.e., Waldenstrom’s macroglobulinemia), hairy cell leukemia (HCL),
  • kidney cancer e.g., nephroblastoma a.k.a. Wilms’ tumor, renal cell carcinoma
  • liver cancer e.g., hepatocellular cancer (HCC), malignant hepatoma
  • lung cancer e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), adenocarcinoma of the lung
  • mastocytosis e.g., systemic
  • mastocytosis muscle cancer
  • myelodysplastic syndrome MDS
  • mesothelioma mesothelioma
  • MPD myeloproliferative disorder
  • PV polycythemia vera
  • ET essential thrombocytosis
  • ALM agnogenic myeloid metaplasia
  • MF myelofibrosis
  • myelofibrosis chronic myelocytic leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)); neuroblastoma; neurofibroma (e.g., neurofibromatosis (NF) type 1 or type 2, schwannomatosis); neuroendocrine cancer (e.g., gastroenteropancreatic neuroendocrinetumor (GEP-NET), carcinoid tumor); osteosarcoma (e.g., bone cancer); ovarian cancer (e.g ., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma); papillary adenocarcinoma; pancreatic cancer (e.g., pancreatic andenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), Islet cell tumors); penile cancer (e.g., Paget’s disease of the penis and scro
  • angiogenesis refers to the formation and the growth of new blood vessels. Normal angiogenesis occurs in the healthy body of a subject for healing wounds and for restoring blood flow to tissues after injury.
  • the healthy body controls angiogenesis through a number of means, e.g., angiogenesis- stimulating growth factors and angiogenesis inhibitors.
  • Many disease states such as cancer, diabetic blindness, age-related macular degeneration, rheumatoid arthritis, and psoriasis, are characterized by abnormal (i.e., increased or excessive) angiogenesis.
  • Abnormal or pathological angiogenesis refers to angiogenesis greater than that in a normal body, especially angiogenesis in an adult not related to normal angiogenesis (e.g., menstruation or wound healing).
  • Abnormal angiogenesis can provide new blood vessels that feed diseased tissues and/or destroy normal tissues, and in the case of cancer, the new vessels can allow tumor cells to escape into the circulation and lodge in other organs (tumor metastases).
  • the angiogenesis is pathological angiogenesis.
  • cardiovascular diseases refers to diseases associated the heart and/or blood vessels.
  • cardiovascular diseases include, but are not limited to, coronary heart disease, stroke or cerebrovascular disease, congenital heart defects, peripheral artery disease, heart disease associated with atherosclerosis, ischemic heart disease, hypertensive heart disease, rheumatic heart disease, cardiac arrhythmias, heart failure, congenital heart disease, inflammatory heart disease, cardiomyopathy, pericardial disease, and valvular heart disease.
  • tissue samples such as tissue sections and needle biopsies of a tissue
  • cell samples e.g ., cytological smears (such as Pap or blood smears) or samples of cells obtained by microdissection); samples of whole organisms (such as samples of yeasts or bacteria); or cell fractions, fragments, or organelles (such as obtained by lysing cells and separating the components thereof by centrifugation or otherwise).
  • biological samples include blood, serum, urine, semen, fecal matter, cerebrospinal fluid, interstitial fluid, mucus, tears, sweat, pus, biopsied tissue (e.g., obtained by a surgical biopsy or needle biopsy), nipple aspirates, milk, vaginal fluid, saliva, swabs (such as buccal swabs), or any material containing biomolecules that is derived from a first biological sample.
  • Biological samples also include those biological samples that are transgenic, such as a transgenic oocyte, sperm cell, blastocyst, embryo, fetus, donor cell, or cell nucleus, or cells or cell lines derived from biological samples.
  • demethylase refers to any enzyme that catalyzes the removal of methyl groups from a substrate (e.g., nucleic acids, proteins (e.g., histones), metabolites, natural products and intermediates thereto, and other compounds).
  • A“histone demethylase” catalyzes the removal of a methyl group from a histone protein.
  • a“histone Lys demethylase,” or“KDM” catalyzes the removal of a methyl group from the N-methyl lysine residue of a histone protein.
  • KDM KDM’s are categorized into two subfamilies: the flavin-dependent KDM1 subfamily, and the 2-oxoglutarate- (20G) dependent JmjC subfamily (KDM2-7 subfamily).
  • the histone demethylase is a KDM.
  • the overexpression of certain KDM’s e.g., KDM’s in the JmjC KDM2-7 subfamily
  • KDM has been linked to cancer.
  • Overexpression of JmjC KDM’s has been observed in multiple types of cancer cells.
  • KDM include, but are not limited to, KDM2/7, KDM3, KDM4, KDM5, and KDM6.
  • KDM5 include KDM5A, KDM5B, and KDM5C.
  • exemplary sequences from GenBank are of Genbank ID 5927, the contents of which are hereby incorporated by reference in their entireties.
  • exemplary sequences from GenBank are of Genbank ID 10765, the contents of which are hereby incorporated by reference in their entireties.
  • exemplary sequences from GenBank are of Genbank ID 8242, the contents of which are hereby incorporated by reference in their entireties.
  • FIG. 1 shows the JmjC KDM family.
  • the positive control compounds for JmjC KDM inhibitors are N-oxalyglycine (“NOG”) and 2,4 pyridinedicarboxylic acid.
  • N-oxalyglycine can be used to substitute 2-oxoglutarate.
  • FIG. 2 shows the protein structure of the 2-OG/(Fe (II)) binding site.
  • FIGs. 3A-3B show data for KDM5 selective inhibitor PCK62 and other exemplary KDM5 inhibitors in a KDM5B_alphascreen activity assay.
  • FIGs. 3A-3B also depict exemplary KDM5 inhibitor PCK62 (JADA62).
  • FIGs. 3A-3B show data for PCK62 against different KDM’s (KDM5A, KDM5B, KDM5C; KDM3A, and KDM3B).
  • PCK62 shows reasonable inhibitory activity of KDM5, as compared to other exemplary KDM5 inhibitors.
  • FIG. 4 shows a Western blot showing the cellular activity of PCK62 and other exemplary KDM5 inhibitors at the indicated concentrations (at 10 mM, 1 mM, and 0.1 pM), against
  • the blot shows increased inhibition of KDM activity (increased change in methylation level) by the exemplary KDM5 inhibitors (including PCK62) against H3K4me3 (KDM5 target that is methylated).
  • FIG. 5 shows a Western blot showing the selectivity of exemplary KDM5 inhibitor PCK62 for KDM5 in the cell.
  • the KDM inhibitory activity of PCK62 against different KDM targets for KDM3, KDM4, KDM5, and KDM6 (H3K4me3, H3K9me3, H3K27me3,
  • H3K36me3 was assayed after treatment with PCK62 (at 1 pM and 3 pM) in the MM.1S (human multiple myeloma) and MOLP8 (human multiple myeloma) cell lines.
  • H3K4me3 is a KDM5 target
  • H3K9me3 is a KDM3 target
  • H3K27me3 is a KDM6 target
  • H3K36me3 is a KDM4 target.
  • the blot shows increased selectivity of PCK62 against KDM5 target H3K4me3 in view of the increased inhibition of KDM5 activity against this KDM5 target, in contrast with the other KDM targets.
  • FIG. 6 shows an in silico model of KDM5B and its interactions with PCK62 (J ADA-62) in docking studies.
  • FIG. 7 shows exemplary KDM5 inhibitors.
  • FIG. 8 shows exemplary KDM5 inhibitors.
  • FIGs. 9A-9B show assay data for exemplary KDM5 inhibitors PCK62 (J ADA-62), JADA172, JADA173, JADA174, JADA175, Morganl, Morgan2, Morgan3, and Morgan4, compounds in a KDM5B_alphascreen activity assay.
  • FIGs. 9A-9B also show the structures of exemplary KDM5 inhibitors PCK62 (JADA-62), JADA172, JADA173, JADA174, JADA175, Morganl, Morgan2, Morgan3, and Morgan4.
  • FIG. 10 shows Western Blot assay data for exemplary KDM5 inhibitors EPT103656, JADA172, JADA173, JADA174, JADA175, Morganl, Morgan2, Morgan3, and Morgan4 (each at a 1 mM concentration) against Anti-H3K4me3 rabbit antibody (KDM5 target) and Anti-H3 rabbit antibody (“H3”; positive control), after a 24 hour incubation.
  • Anti-H3K4me3 Rabbit Ab concentration is 1:2000 and Anti-H3 Rabbit Ab concentration is 1:8000.
  • FIG. 11 shows a 5-day growth inhibition CellTiter-Glo Luminescent Cell Viability (CTG) assay upon treatment of MM.1S (human multiple myeloma) cell line, with exemplary KDM5 inhibitors JADA-62 (PCK62), and JADA82 (PCK82; of the structure:
  • FIG 12 shows the normalized total flux over 17 days from bioluminescence imaging of mice injected with luciferized molp8 cells. Also shown is the survival proportions of mice treated with PCK82 vs control.
  • the present disclosure provides inhibitors of histone demethylases.
  • the inhibitors are selective inhibitors.
  • the histone demethylase is a KDM.
  • the KDM is a KDM5.
  • the compounds disclosed herein inhibit the activity of KDM’s.
  • the compounds disclosed herein inhibit the activity of KDM5.
  • the compounds disclosed herein specifically inhibit the activity of KDM5.
  • the compounds disclosed herein inhibit the activity of KDM5.
  • the compounds disclosed herein selectively inhibit the activity of KDM5.
  • the histone demethylase is a KDM. In certain embodiments, the KDM is a KDM5. In certain embodiments, the use is as a therapeutic. In certain embodiments, the therapeutic use is the treatment and/or prevention of diseases associated with the overexpression and/or aberrant activity of a histone demethylase. In certain embodiments, the histone demethylase is a KDM. In certain embodiments, the KDM is KDM5. In certain embodiments, the compounds covalently inhibit KDM’s. In certain embodiments, the diseases treated and/or prevented include, but are not limited to, proliferative diseases and/or cardiovascular diseases. The proliferative diseases include, but are not limited to, cancer. In certain embodiments, the cancer is lung cancer. In certain embodiments, the cancer is breast cancer. In certain
  • the cancer is liver cancer. In certain embodiments, the cancer is pancreatic cancer. In certain embodiments, the cancer is gastric cancer. In certain embodiments, the cancer is ovarian cancer. In certain embodiments, the cancer is colon cancer. In certain embodiments, the cancer is colorectal cancer. In certain embodiments, the cancer is a carcinoma. In certain embodiments, the cancer is multiple myeloma. In certain embodiments, the cancer is Ewing’s sarcoma. In certain embodiments, the cancer is a cancer that begins in the skin or tissues lining or covering internal organs (a“carcinoma”). In certain embodiments, the carcinoma is a carcinoma of the breast, liver, lung, pancreas, stomach, colon, or prostate. In certain
  • the cancer is associated with the overexpression and/or aberrant activity of a histone demethylase.
  • the histone demethylase is a KDM.
  • the KDM is KDM5.
  • the compounds selectively inhibit a histone demethylase.
  • the histone demethylase is a KDM.
  • the KDM is KDM5.
  • the compounds selectively inhibit KDM5.
  • the compounds selectively inhibit KDM5B.
  • the cardiovascular diseases include, but are not limited to, heart disease.
  • the heart disease is coronary heart disease.
  • the heart disease is stroke.
  • the heart disease is cerebrovascular disease.
  • the heart disease is congenital heart defects.
  • the heart disease is peripheral artery disease.
  • the compounds described herein may be useful in treating and/or preventing diseases or inhibiting the activity of a histone demethylase in a subject or biological sample.
  • the disease is a proliferative disease.
  • the disease is cancer.
  • the disease is cardiovascular disease.
  • the disease is a disease associated with the activity of a histone demethylase in a subject.
  • the histone demethylase is a KDM.
  • the KDM is KDM5.
  • a compound described herein is a compound of Formulae (I), (II), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
  • a compound described herein is a compound of Formulae (I), (II), or a pharmaceutically acceptable salt thereof.
  • R 1 is hydrogen, optionally substituted alkyl, or a nitrogen protecting group
  • R 1B is hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, or a nitrogen protecting group
  • each instance of R 2 is independently optionally substituted alkyl or a nitrogen protecting group
  • each instance of R 3 is independently halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -CN, -SCN, -NO2, -N 3 , -OR A , -N(R B ) 2 , or -SR A ;
  • each instance of R A is independently hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom;
  • each instance of R B is independently hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group; or optionally two instances of R B are taken together with their intervening atoms to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring;
  • n 0, 1, 2, or 3;
  • z is 0 or 1 ;
  • X is -N(R 1A )- or -0-;
  • L is -C(R 6 ) 2 -;
  • each instance of R 6 is independently hydrogen, halogen, or optionally substituted alkyl; each instance of R 1A is independently hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted carbocyclyl, or a nitrogen protecting group; and ring is optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted carbocyclyl, or optionally substituted aryl;
  • the compound of Formula (I) is a compound of Formula (I-A):
  • each instance of R 4 is independently halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -CN, - SCN, -NO2, -N 3 , -OR a , -N(R b ) 2 , or -SR A , or optionally two instances of R 4 are taken together with their intervening atoms to form a substituted or unsubstituted carbocyclic ring, substituted or unsubstituted aryl ring, substituted or unsubstituted heterocyclic ring, or substituted or unsubstituted heteroaryl ring; and
  • the compound of Formula (I) is a compound of Formula (I-B):
  • each instance of R 4 is independently optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -OR A , -N(R B ) 2 , or - SR a , or optionally two instances of R 4 are taken together with their intervening atoms to form a substituted or unsubstituted carbocyclic ring, substituted or unsubstituted aryl ring, substituted or unsubstituted heterocyclic ring, or substituted or unsubstituted heteroaryl ring; and
  • x is 0, 1, 2, 3, 4, or 5; and the other substituents R 1 , R 1A , R 1B , and R 2 are as defined herein.
  • the compound is a compound of Formula (II):
  • R 1 is independently hydrogen, optionally substituted alkyl, or a nitrogen protecting group
  • R 1B is independently hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, or a nitrogen protecting group
  • each instance of R A is independently hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom;
  • each instance of R B is independently hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group; or optionally two instances of R B are taken together with their intervening atoms to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring;
  • n 0, 1, 2, or 3;
  • R 7 is hydrogen or optionally substituted alkyl.
  • R 1 is hydrogen
  • R 1 is optionally substituted alkyl.
  • R 1 is substituted or unsubstituted Ci -6 alkyl. In certain embodiments, R 1 is substituted or unsubstituted methyl. In certain embodiments, R 1 is unsubstituted methyl. In certain embodiments, R 1 is substituted or unsubstituted ethyl. In certain embodiments, R 1 is substituted or unsubstituted propyl.
  • R 1 is a nitrogen protecting group.
  • R 1 is benzyl (“Bn”).
  • R 1 is //77-butyl carbonate (“BOC” or“Boc”).
  • R 1 is benzyl carbamate (“Cbz”).
  • R 1 is 9-fluorenylmethyl carbonate (“Fmoc”).
  • R 1 is trifluoroacetyl.
  • R 1 is triphenylmethyl.
  • R 1 is acetyl.
  • R 1 is p- toluenesulfonamide (“Ts”).
  • R 1B is hydrogen.
  • R 1B is optionally substituted alkyl. In certain embodiments, R 1B is substituted or unsubstituted Ci -6 alkyl. In certain embodiments, R 1B is optionally substituted Ci- 6 alkyl. In certain embodiments, R 1B is substituted or unsubstituted methyl. In certain embodiments, R 1B is unsubstituted methyl. In certain embodiments, R 1B is substituted or unsubstituted ethyl. In certain embodiments, R 1B is unsubstituted ethyl. In certain embodiments, R 1B is not unsubstituted ethyl. In certain embodiments, R 1B is unsubstituted methyl or
  • R 1B is not ethyl. In certain embodiments, R 1B is substituted or unsubstituted propyl. In certain embodiments, R 1B is unsubstituted iso-propyl.
  • R 1B is not ethyl.
  • R 1B is substituted or unsubstituted carbocyclyl. In certain embodiments, R 1B is substituted or unsubstituted, 3- to 7-membered, monocyclic carbocyclyl comprising zero, one, or two double bonds in the carbocyclic ring system. In certain
  • R 1B is optionally substituted carbocyclyl. In certain embodiments, R 1B is optionally substituted cyclopropyl. In certain embodiments, R 1B is unsubstituted cyclopropyl.
  • R 1B is substituted or unsubstituted aryl. In certain embodiments, R 1B is substituted or unsubstituted, 6- to lO-membered aryl. In certain embodiments, R 1B is benzyl. In certain embodiments, R 1B is substituted or unsubstituted phenyl.
  • R 1B is substituted or unsubstituted heteroaryl.
  • R 1B is substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur.
  • R 1B is substituted or unsubstituted, 9- to 10- membered, bicyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur.
  • R 1B is a nitrogen protecting group.
  • the nitrogen protecting group is Bn, BOC, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts.
  • both instances of R 2 are the same. In certain embodiments, each instance of R 2 is different.
  • At least one instance of R 2 is optionally substituted alkyl. In some embodiments, at least one instance of R 2 is substituted or unsubstituted Ci -6 alkyl. In certain embodiments, at least one instance of R 2 is optionally substituted Ci -6 alkyl. In certain embodiments, at least one instance of R 2 is substituted or unsubstituted methyl. In certain embodiments, at least one instance of R 2 is unsubstituted methyl. In certain embodiments, both instances of R 2 are substituted or unsubstituted methyl. In certain embodiments, both instances of R 2 are unsubstituted methyl.
  • At least once instance of R 2 is substituted or unsubstituted ethyl. In certain embodiments, at least one instance of R 2 is not substituted or unsubstituted ethyl. In certain embodiments, both instances of R 2 are not ethyl. In certain embodiments, at least one instance of R 2 is substituted or unsubstituted propyl. In certain embodiments, at least one instance of R 2 is unsubstituted n-propyl. In certain embodiments, at least one instance of R 2 is unsubstituted methyl or isopropyl.
  • each R 2 is independently optionally substituted alkyl or a nitrogen protecting group. In certain embodiments, each R 2 is independently optionally substituted alkyl or a nitrogen protecting group. In certain embodiments, R 2 is Bn, BOC, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts. In certain embodiments, at least one instance of R 2 is a nitrogen protecting group. In some embodiments, the nitrogen protecting group is Bn, BOC, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts.
  • the compound includes no instances of substituent R 3 . In certain embodiments, the compound includes one or more instances of substituent R 3 .
  • n is 0. In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, n is 3.
  • At least one instance of R 3 is a halogen.
  • At least one instance of R 3 is F. In certain embodiments, at least one instance of R 3 is Cl. In certain embodiments, at least one instance of R 3 is Br. In certain embodiments, at least one instance of R 3 is I.
  • At least one instance of R 3 is optionally substituted acyl.
  • At least one instance of R 3 is optionally substituted alkyl.
  • the alkyl is substituted or unsubstituted Ci- 6 alkyl.
  • at least one instance of R 3 is substituted or unsubstituted methyl.
  • at least one instance of R 3 is substituted or unsubstituted ethyl.
  • at least one instance of R 3 is substituted or unsubstituted propyl.
  • at least one instance of R 3 is optionally substituted alkenyl.
  • the alkenyl is substituted or unsubstituted C 2-6 alkenyl.
  • At least one instance of R 3 is optionally substituted alkynyl.
  • the alkynyl is substituted or unsubstituted C2-6 alkynyl.
  • At least one instance of R 3 is optionally substituted carbocyclyl.
  • the carbocyclyl is substituted or unsubstituted, 3- to 7-membered, monocyclic carbocyclyl comprising zero, one, or two double bonds in the carbocyclic ring system.
  • at least one instance of R 3 is optionally substituted heterocyclyl.
  • the heterocyclyl is substituted or unsubstituted, 5- to lO-membered monocyclic or bicyclic heterocyclic ring, wherein one or two atoms in the heterocyclic ring are independently nitrogen, oxygen, or sulfur.
  • At least one instance of R 3 is optionally substituted aryl.
  • the aryl is substituted or unsubstituted, 6- to lO-membered aryl.
  • at least one instance of R 3 is benzyl.
  • at least one instance of R 3 is substituted or unsubstituted phenyl.
  • at least one instance of R 3 is optionally substituted heteroaryl.
  • At least one instance of R 3 is substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur; or substituted or unsubstituted, 9- to lO-membered, bicyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur.
  • At least one instance of R 3 is -OR A .
  • R A is -OH.
  • R A is -OMe.
  • at least one instance of R 3 is -N(R B ) 2 .
  • at least one instance of R 3 is -NMe 2 .
  • At least one instance of R 3 is -SR A . In certain embodiments, at least one instance of R 3 is -SMe.
  • At least one instance of R 3 is-CN.
  • At least one instance of R 3 is -SCN.
  • At least one instance of R 3 is— N0 2 .
  • At least one instance of R 3 is -N 3 .
  • At least one instance of R 3 is -OR A , wherein each instance of R A is independently hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom.
  • At least one instance of R 3 is N(R B ) 2 , wherein each instance of R B is independently hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group; or optionally two instances of R B are taken together with their intervening atoms to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring.
  • R A is hydrogen
  • R A is substituted or unsubstituted alkyl.
  • R A is substituted or unsubstituted Ci -6 alkyl. In certain embodiments, R A is substituted or unsubstituted methyl. In certain embodiments, R A is substituted or unsubstituted ethyl. In certain embodiments, R A is substituted or unsubstituted propyl.
  • R A is substituted or unsubstituted alkenyl.
  • R A is substituted or unsubstituted C2-6 alkenyl.
  • R A is substituted or unsubstituted alkynyl. In certain embodiments, R A is substituted or unsubstituted C2-6 alkynyl.
  • R A is substituted or unsubstituted carbocyclyl. In certain embodiments, R A is substituted or unsubstituted, 3- to 7-membered, monocyclic carbocyclyl comprising zero, one, or two double bonds in the carbocyclic ring system.
  • R A is substituted or unsubstituted heterocyclyl. In certain embodiments, R A is substituted or unsubstituted, 5- to lO-membered monocyclic or bicyclic heterocyclic ring, wherein one or two atoms in the heterocyclic ring are independently nitrogen, oxygen, or sulfur. [00145] In certain embodiments, R A is substituted or unsubstituted aryl. In certain embodiments, R A is substituted or unsubstituted, 6- to lO-membered aryl. In certain embodiments, R A is benzyl. In certain embodiments, R A is substituted or unsubstituted phenyl.
  • R A is substituted or unsubstituted heteroaryl.
  • R A is substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur; or substituted or unsubstituted, 9- to lO-membered, bicyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur.
  • R A is an oxygen protecting group when attached to an oxygen atom.
  • R A is a sulfur protecting group when attached to a sulfur atom.
  • At least one instance of R B is hydrogen.
  • At least one R B is substituted or unsubstituted alkyl. In certain embodiments, at least one R B is substituted or unsubstituted Ci -6 alkyl. In certain embodiments, at least one instance of R B is substituted or unsubstituted methyl. In certain embodiments, at least one instance of R B is substituted or unsubstituted ethyl. In certain embodiments, at least one instance of R B is substituted or unsubstituted propyl.
  • At least one instance of R B is substituted or unsubstituted alkenyl. In certain embodiments, at least one instance of R B is substituted or unsubstituted C 2-6 alkenyl).
  • At least one instance of R B is substituted or unsubstituted alkynyl. In certain embodiments, at least one instance of R B is substituted or unsubstituted C2-6 alkynyl.
  • At least one instance of R B is substituted or unsubstituted carbocyclyl. In certain embodiments, at least one instance of R B is substituted or unsubstituted,
  • At least one instance of R B is monocyclic carbocyclyl comprising zero, one, or two double bonds in the carbocyclic ring system. [00155] In certain embodiments, at least one instance of R B is substituted or unsubstituted heterocyclyl. In certain embodiments, at least one instance of R B is substituted or unsubstituted, 5- to lO-membered monocyclic or bicyclic heterocyclic ring, wherein one or two atoms in the heterocyclic ring are independently nitrogen, oxygen, or sulfur.
  • At least one instance of R B is substituted or unsubstituted aryl.
  • At least one instance of R B substituted or unsubstituted, 6- to 10- membered aryl. In certain embodiments, at least one instance of R B is benzyl. In certain embodiments, at least one instance of R B is substituted or unsubstituted phenyl.
  • At least one instance of R B is substituted or unsubstituted heteroaryl. In certain embodiments, at least one instance of R B is substituted or unsubstituted, 5- to 6-membered. In certain embodiments, at least one instance of R B is monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur. In certain embodiments, at least one instance of R B is substituted or unsubstituted, 9- to lO-membered, bicyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur.
  • At least one instance of R B is a nitrogen protecting group. In certain embodiments, at least one instance of R B is Bn. In certain embodiments, at least one instance of R B is BOC. In certain embodiments, at least one instance of R B is Cbz. In certain embodiments, at least one instance of R B is Fmoc. In certain embodiments, at least one instance of R B is trifluoroacetyl. In certain embodiments, at least one instance of R B is triphenylmethyl. In certain embodiments, at least one instance of R B is acetyl. In certain embodiments, at least one instance of R B is Ts. In certain embodiments, two instances of R B are taken together with their intervening atoms to form a substituted or unsubstituted heterocyclic ring. In certain
  • two instances of R B are substituted or unsubstituted, 5- to lO-membered monocyclic or bicyclic heterocyclic ring, wherein one or two atoms in the heterocyclic ring are independently nitrogen, oxygen, or sulfur.
  • At least one instance of R B is substituted or unsubstituted heteroaryl ring. In certain embodiments, at least one instance of R B is substituted or
  • At least one instance of R B is monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur. In certain embodiments, at least one instance of R B is substituted or unsubstituted, 9- to lO-membered, bicyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur.
  • substituent X is -N(R 1A ) -, wherein each instance of R 1A is independently hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, or a nitrogen protecting group.
  • substituent X is -NH-.
  • substituent X is -0-.
  • R 1A is hydrogen
  • R 1A is substituted or unsubstituted acyl.
  • R 1A is substituted or unsubstituted alkyl.
  • R 1A is substituted or unsubstituted Ci -6 alkyl. In certain embodiments, R 1A is substituted or unsubstituted methyl. In certain embodiments, R 1A is substituted or unsubstituted ethyl. In certain embodiments, R 1A is substituted or unsubstituted propyl.
  • R 1A is substituted or unsubstituted alkenyl. In certain embodiments, R 1A is substituted or unsubstituted C 2-6 alkenyl..
  • R 1A is substituted or unsubstituted alkynyl. In certain embodiments, R 1A is substituted or unsubstituted C2-6 alkynyl.
  • R 1A is substituted or unsubstituted carbocyclyl. In certain embodiments, R 1A is substituted or unsubstituted, 3- to 7-membered, monocyclic carbocyclyl comprising zero, one, or two double bonds in the carbocyclic ring system.
  • R 1A is a nitrogen protecting group. In certain embodiments, R 1A is Bn. In certain embodiments, R 1A is BOC. In certain embodiments, R 1A is Cbz. In certain embodiments, R 1A is Fmoc. In certain embodiments, R 1A is trifluoroacetyl. In certain embodiments,
  • R 1A is triphenylmethyl. In certain embodiments, R 1A is acetyl. In certain embodiments, R 1A is Ts.
  • Formula (I) includes zero instances of linker L. In certain embodiments, Formula (I) includes one instance of linker L.
  • linker L is - C(R 6 ) 2 -, wherein each instance of R 6 is independently hydrogen, halogen, or optionally substituted alkyl. [00172] In certain embodiments, linker L is -(CH 2 )-.
  • z is 0. In certain embodiments, z is 1.
  • At least one instance of R 6 is hydrogen. In certain embodiments, both instances of R 6 are hydrogen.
  • At least one instance of R 6 is halogen. In certain embodiments, at least one instance of R 6 is F. In certain embodiments, at least one instance of R 6 is Cl. In certain embodiments, at least one instance of R 6 is Br. In certain embodiments, at least one instance of R 6 is I.
  • At least one instance of R 6 is optionally substituted alkyl. In certain embodiments, at least one instance of R 6 is substituted or unsubstituted Ci -6 alkyl. In certain embodiments, at least one instance of R 6 is substituted or unsubstituted methyl. In certain embodiments, at least one instance of R 6 is substituted or unsubstituted ethyl. In certain embodiments, at least one instance of R 6 is substituted or unsubstituted propyl.
  • the moiety is -C(R ) 2 (optionally substituted heteroaryl), wherein each instance of R 6 is independently hydrogen, halogen, or optionally substituted alkyl.
  • the moiety is -C(R 6 ) 2 (optionally substituted aryl), wherein R 6 is as defined herein.
  • the moiety is -CH 2 (optionally substituted heterocyclyl).
  • the moiety r 'r > is -CH 2 (substituted or unsubstituted
  • the moiety @r y is -CH 2 (optionally substituted heteroaryl).
  • the moiety > is -CH 2 (substituted or unsubstituted,
  • the moiety (7V ⁇ L)z V is -CH 2 (optionally substituted 5- membered heterocyclyl).
  • the moiety (7V ⁇ L)z V is -CH 2 (optionally substituted 5- membered heteroaryl).
  • the moiety (7V ⁇ L)z V is -CH 2 (optionally substituted 5- membered heterocyclyl) or -CH 2 (optionally substituted 5-membered heteroaryl).
  • the moiety -CH 2 (optionally substituted 1,3- dioxol-2-one).
  • the moiety -CH 2 (optionally substituted 1,3- dioxol-2-one), wherein the l,3-dioxol-2-one is optionally substituted with R x , and R x is optionally substituted acyl, optionally substituted alkyl, -0(optionally substituted alkyl), or - N0 2 .
  • the moiety l > is of the formula: . wherein R x is optionally substituted acyl, optionally substituted alkyl, -0(optionally substituted alkyl), or -NO2, and a is 0 or 1.
  • R x is optionally substituted acyl, optionally substituted alkyl, -0(optionally substituted alkyl), or -NO2, and a is 0 or 1.
  • the moiety i of the formula certain embodiments, the moiety -CH 2 (optionally substituted dioxolane).
  • the moiety ⁇ r-> i , s -CH 2 (optionally substituted oxazolidin-2-one) .
  • the moiety ⁇ is -CH 2 (5-6 membered heterocyclyl), where the heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the moiety -CH 2 (5-6 membered heterocyclyl), where the heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • ring is optionally substituted carbocyclyl.
  • ring is substituted or unsubstituted, 3- to 7-membered, monocyclic carbocyclyl comprising zero, one, or two double bonds in the carbocyclic ring system.
  • ring is optionally substituted aryl.
  • z is 0; and ring is optionally substituted phenyl.
  • ring is optionally substituted phenyl.
  • z is 0; and ring is of the formula: , wherein x is 2, and two instances of R 4 are taken together with their intervening atoms to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring.
  • z is 0; and ring is of the formula: , wherein x is 2, and two instances of R 4 are taken together with their intervening atoms to form a substituted or unsubstituted heterocyclic ring.
  • z is 0; and ring is of the
  • z is 0; and ring is of the formula: , wherein x is 2, and two instances of R 4 are taken together with their intervening atoms to form a substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur; or substituted or unsubstituted, 9- to lO-membered, bicyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur.
  • z is 0; and ring is of the formula: optionally substituted acyl, optionally substituted alkyl, -0(optionally substituted alkyl), or -N0 2 ; and y is 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9, as valency
  • z is 0; and ring of the formula:
  • z is 0; and ring of the formula:
  • z is 0; and ring of the formula:
  • ring Formula (I) includes no instances of substituent
  • ring in Formula (I) includes one or more instances of substituent R 4 . In certain embodiments, all instances of R 4 are the same. In certain embodiments, two instances of R 4 are the same. In certain embodiments, each instance of R 4 is different.
  • x is 0. In certain embodiments, x is 1. In certain embodiments, x is 2. In certain embodiments, x is 3. In certain embodiments, x is 4. In certain embodiments, x is 5.
  • At least one instance of R 4 is halogen. In certain embodiments, at least one instance of R 4 is F. In certain embodiments, at least one instance of R 4 is Cl. In certain embodiments, at least one instance of R 4 is Br. In certain embodiments, at least one instance of R 4 is I.
  • At least one instance of R 4 is optionally substituted alkenyl. In certain embodiments, at least one instance of R 4 is substituted or unsubstituted C 2-6 alkenyl. In
  • At least one instance of R 4 is of the formula: ⁇ wherein: R x is optionally substituted acyl, optionally substituted alkyl, -0(optionally substituted alkyl), or -
  • R x is -C0 2 H.
  • R x is -C0 2 (optionally substituted Ci -6 alkyl). In certain embodiments, R x is -N0 2 .
  • At least one instance of R 4 is of the formula:
  • At least one instance of R 4 is of the formula: .
  • At least one instance of R 4 is of the formula:
  • At least one instance of R 4 is of the formula:
  • At least one instance of R 4 is optionally substituted alkynyl. In certain embodiments, at least one instance of R 4 is substituted or unsubstituted C 2-6 alkynyl.
  • At least one instance of R 4 is optionally substituted carbocyclyl. In certain embodiments, at least one instance of R 4 is substituted or unsubstituted, 3- to 7- membered, monocyclic carbocyclyl comprising zero, one, or two double bonds in the
  • At least one instance of R 4 is optionally substituted heterocyclyl. In certain embodiments, at least one instance of R 4 is substituted or unsubstituted, 5- to 10- membered monocyclic or bicyclic heterocyclic ring, wherein one or two atoms in the heterocyclic ring are independently nitrogen, oxygen, or sulfur.
  • At least one instance of R 4 is optionally substituted aryl. In certain embodiments, at least one instance of R 4 is substituted or unsubstituted, 6- to 10- membered aryl. In certain embodiments, at least one instance of R 4 is benzyl. In certain embodiments, at least one instance of R 4 is substituted or unsubstituted phenyl.
  • At least one instance of R 4 is optionally substituted heteroaryl.
  • At least one instance of R 4 is substituted or unsubstituted, 5- to 6- membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur; or substituted. In certain embodiments, at least one instance of R 4 is unsubstituted, 9- to lO-membered, bicyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur.
  • At least one instance of R 4 is -OR A . In certain embodiments, at least one instance of R 4 is -OH. In certain embodiments, at least one instance of R 4 is -OMe. In certain embodiments, at least one instance of R 4 is -OiPr. In certain embodiments, at least one instance of R 4 is -OR A , and R A is hydrogen, optionally substituted Ci -6 alkyl, or optionally substituted aryl. In certain embodiments, at least one instance of R 4 is -OH. In certain embodiments, two instances of R 4 are -OH.
  • At least one instance of R 4 is -0(optionally substituted Ci -6 alkyl). In certain embodiments, at least one instance of R 4 is -OMe. In certain embodiments, two instances of R 4 are -OMe. In certain embodiments, R 4 is not -OMe. In certain embodiments, at least one instance of R 4 is -OEt. In certain embodiments, two instances of R 4 are -OEt. In certain embodiments, at least one instance of R 4 is -O(n-propyl). In certain embodiments, two instances of R 4 are -O(n-propyl). In certain embodiments, at least one instance of R 4 is -O(isopropyl).
  • two instances of R 4 are -O(isopropyl). In certain embodiments, at least one instance of R 4 is -O(n-butyl). In certain embodiments, two instances of R 4 are -O(n-butyl). In certain embodiments, at least one instance of R 4 is -O(t-butyl). In certain embodiments, two instances of R 4 are -0(/ ⁇ ? / 7-butyl). In certain embodiments, at least one instance of R 4 is -0(n- pentyl). In certain embodiments, two instances of R 4 are -O(n-pcntyl).
  • At least one instance of R 4 is -0(optionally substituted aryl). In certain embodiments, at least one instance of R 4 is -0(optionally substituted phenyl). In certain embodiments, at least one instance of R 4 is -0(unsubstituted phenyl). In certain embodiments, two instances of R 4 are -0(optionally substituted phenyl). In certain embodiments, two instances of R 4 are -0(unsubstituted phenyl).
  • At least one instance of R 4 is -N(R B ) 2 . In certain embodiments, at least one instance of R 4 is -NMe 2 . In certain embodiments, at least one instance of R 4 is - NH(optionally substituted alkyl). In certain embodiments, at least one instance of R 4 is - NH(optionally substituted acyl).
  • At least one instance of R 4 is -SR A . In certain embodiments, at least one instance of R 4 is -SMe.
  • At least one instance of R 4 is -CN.
  • At least one instance of R 4 is -SCN. In certain embodiments, at least one instance of R 4 is -N0 2 .
  • At least one instance of R 4 is -N 3 .
  • two instances of R 4 are taken together with their intervening atoms to form a substituted or unsubstituted carbocyclyl. In certain embodiments, two instances of R 4 are taken together with their intervening atoms to form a substituted or unsubstituted, 3- to 7-membered, monocyclic carbocyclyl comprising zero, one, or two double bonds in the carbocyclic ring system. In certain embodiments, two instances of R 4 are taken together with their intervening atoms to form a substituted or unsubstituted aryl.
  • two instances of R 4 are taken together with their intervening atoms to form a substituted or unsubstituted, 6- to lO-membered aryl. [00229] In certain embodiments, two instances of R 4 are taken together with their intervening atoms to form a substituted or unsubstituted heterocyclic ring. In certain embodiments, two instances of R 4 are taken together with their intervening atoms to form a substituted or unsubstituted, 5- to lO-membered monocyclic or bicyclic heterocyclic ring, wherein one or two atoms in the heterocyclic ring are independently nitrogen, oxygen, or sulfur.
  • two instances of R 4 are taken together with their intervening atoms to form a substituted or unsubstituted heteroaryl ring. In certain embodiments, two instances of R 4 are taken together with their intervening atoms to form a substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur.
  • two instances of R 4 are taken together with their intervening atoms to form a substituted or unsubstituted, 9- to lO-membered, bicyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur.
  • substituent R x on ring , there are no instances of substituent R x . In certain embodiments, there are one or more instances of substituent R x . In certain embodiments, there are y number of instances of substituent R x , as valency permits.
  • substituent R x is the same as substituent R 4 .
  • y is 0. In certain embodiments, y is 1. In certain embodiments, y is 2. In certain embodiments, y is 3. In certain embodiments, y is 4. In certain embodiments, y is 5. In certain embodiments, y is 6. In certain embodiments, y is 7. In certain embodiments, y is 8. In certain embodiments, y is 9.
  • At least one instance of R x is optionally substituted alkyl. In certain embodiments, at least one instance of R x is substituted or unsubstituted Ci -6 alkyl. In certain embodiments, at least one instance of R x is substituted or unsubstituted methyl. In certain embodiments, at least one instance of R x is substituted or unsubstituted ethyl. In certain embodiments, at least one instance of R x is unsubstituted ethyl. In certain embodiments, at least one instance of R x is substituted or unsubstituted propyl. In certain embodiments, at least one instance of R x is unsubstituted n-propyl. In certain embodiments, at least one instance of R x is unsubstituted methyl or isopropyl.
  • At least one instance of R x is -0(optionally substituted alkyl). In certain embodiments, at least one instance of R x is -0(optionally substituted Ci- 6 alkyl).
  • At least one instance of R x is -OMe.
  • two instances of R x are -OMe. In certain embodiments, at least one instance of R x is -OEt. In certain embodiments, two instances of R x are -OEt. In certain embodiments, at least one instance of R x is -O(n-propyl). In certain embodiments, two instances of R x are -0(n- propyl). In certain embodiments, at least one instance of R x is -O(isopropyl). In certain embodiments, two instances of R x are -O(isopropyl). In certain embodiments, at least one instance of R x is -O(n-butyl). In certain embodiments, two instances of R x are -O(n-butyl).
  • At least one instance of R x is -0(/ ⁇ ? /7-butyl). In certain embodiments, two instances of R x are -O(ieri-butyl). In certain embodiments, at least one instance of R x is -0(n- pentyl). In certain embodiments, two instances of R x are -O(n-pentyl).
  • At least one instance of R x is -N0 2 .
  • z is 0; and ring is of the formula:
  • ring optionally substituted aryl. In certain embodiments, ring substituted or unsubstituted, 6- to lO-membered aryl. In certain embodiments, z is 0; and ring optionally substituted aryl. In certain embodiments, z is 0; and ring substituted or unsubstituted, 6- to lO-membered aryl. In certain embodiments, z ( A
  • z is 0; and ring benzyl.
  • z is 0; and ring ⁇ — / is substituted or unsubstituted phenyl.
  • z is 0; and ring of the formula: , wherein:
  • R x is optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl,
  • z is 0; and ring of the
  • R x is optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, -
  • z is 0; and ring of the
  • z is 0; and ring of the formula:
  • z is 0; and ring of the formula:
  • z is 0; and ring v A ) is of the formula: certain embodiments, z
  • z is 0; and ring .
  • z is 0; and ring ⁇ — ') is of the ,
  • z is 0; and ring of the formula: rtain embodiments, z is 0; and ring of the formula:
  • z is 0; and ring of the formula: In certain Substituent R x is defined above. In certain embodiments, z is 0; and ring of the formula:
  • z is 0; and ring of the formula:
  • z is 0; and ring of the formula: .
  • z is 0; and ring of the formula: certain embodiments, z
  • OMe is 0; and ring of the formula ,: : o .
  • z is 0; and ring
  • z is 0; and ring is of the formula:
  • z is 0; and ring ⁇ — ' is of the formula: .
  • z is 0; and ring of the formula: .
  • z is 0; and ring of the formula: .
  • z is 0; and ring certain
  • z is 0; and ring optionally substituted heteroaryl. In certain embodiments, z is 0; and ring substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur. In certain embodiments, z is 0; and ring
  • substituent X is O, z is 0, and ring optionally substituted aryl. In certain embodiments, substituent X is O, z is 0, and ring substituted or unsubstituted, 6- to lO-membered aryl. In certain embodiments, substituent X is O, z is 0, and ring optionally substituted phenyl.
  • substituent X is -N(R 1A )-, wherein each instance of R 1A is independently hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, or a nitrogen protecting group; z is 0; and ring optionally substituted aryl. In certain embodiments, ring is substituted or unsubstituted, 6- to 10- membered aryl.
  • substituent X is -NH-, z is 0, and ring optionally substituted aryl. In certain embodiments, substituent X is -NH-, z is 0, and ring
  • substituent X is -
  • NH-, z is 0, and ring optionally substituted phenyl.
  • substituent X when substituent X is -NH-, z is 0, ring not optionally substituted heterocyclyl. In certain embodiments, when substituent X is -NH-, z is 0, ring is not optionally substituted heteroaryl.
  • substituent X when substituent X is -NH-, z is 0, ring not substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur.
  • the compound of Formula (I) is a compound of the formula:
  • the compound of Formula (I) is a compound of the formula:
  • the compound of Formula (I) is a compound of the formula:
  • R 7 is hydrogen
  • R 7 is optionally substituted alkyl. In certain embodiments, R 7 is substituted or unsubstituted Ci -6 alkyl. In certain embodiments, R 7 is substituted or unsubstituted methyl. In certain embodiments, R 7 is unsubstituted methyl. In certain embodiments, R 7 is substituted or unsubstituted ethyl. In certain embodiments, R 7 is substituted ethyl. In certain embodiments, R 7 is unsubstituted ethyl. In certain embodiments, R 7 is substituted or
  • the compound of Formula (II) is a compound of the formula:
  • the compound of Formula (II) is not of the formula:
  • the compound of Formulae (I) or (II) is a compound provided in any one of the Examples below.
  • a compound described herein is a compound of Formulae (I), (II), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
  • a compound described herein is a compound of Formula (I) or (P), or a pharmaceutically acceptable salt thereof.
  • Certain compounds described herein bind, covalently modify, and/or inhibit a histone demethylase.
  • the compounds described herein irreversibly inhibit a KDM histone demethylase.
  • the compounds described herein reversibly inhibit a KDM histone demethylase.
  • the histone demethylase is a KDM.
  • the histone demethylase is KDM5.
  • the histone demethylase is KDM3.
  • the compounds described herein covalently bind to the histone demethylase.
  • the compounds described herein reversibly bind to the histone demethylase.
  • the compounds described herein non- reversibly bind to the histone demethylase. In certain embodiments, the compounds described herein modulate the activity of a histone demethylase. In certain embodiments, the compounds described herein inhibit the activity of a histone demethylase. In certain embodiments, the compounds described herein specifically inhibit the activity of a histone demethylase. In certain embodiments, the compounds described herein selectively inhibit the activity of a histone demethylase over another histone demethylase for example, but not limited to KDM2/7, KDM3, KDM4, or KDM6. In certain embodiments, the histone demethylase is a KDM. In certain embodiments, the KDM is KDM5. In certain embodiments, the KDM is another KDM. In certain embodiments, the KDM is KDM2/7. In certain embodiments, the KDM is KDM3. In certain embodiments, the KDM is KDM 4. In certain embodiments, the KDM is KDM 6.
  • the binding affinity of a compound described herein to a histone demethylase may be measured by the dissociation constant (K d ) value of an adduct of the compound and the histone demethylase using methods known in the art.
  • the binding affinity is hound with isothermal titration calorimetry (ITC)).
  • the histone demethylase is a KDM.
  • the KDM is KDM5.
  • the K d value of the adduct is not more than about 100 mM, not more than about 10 mM, not more than about 1 mM, not more than about 100 nM, not more than about 10 nM, or not more than about 1 nM.
  • the activity of a histone demethylase is inhibited by a compound described herein.
  • the inhibition of the activity of a histone demethylase by a compound described herein may be measured by determining the half maximal inhibitory concentration (IC 50 ) of the compound when the compound, or a pharmaceutical composition thereof, is contacted with the histone demethylase.
  • the histone demethylase is a KDM.
  • the KDM is KDM5.
  • the IC 50 values may be obtained using methods known in the art. in certain embodiments, the IC 50 values are obtained using a competition binding assay. In certain embodiments, the IC 50 values are obtained using a alphascreen activity assay.
  • the IC 50 value of a compound described herein is not more than about 1 mM, not more than about 100 mM, not more than about 10 mM, not more than about 1 mM, not more than about 100 nM, not more than about 10 nM, or not more than about 1 nM.
  • the compounds described herein may selectively modulate the activity of a histone demethylase.
  • the compounds selectively inhibit the activity of a histone demethylase.
  • the compounds inhibit the activity of two or more histone demethylases to the same extent.
  • the histone demethylase is a KDM.
  • the KDM is KDM5.
  • the selectivity of a compound described herein in inhibiting the activity of a first histone demethylase over a second histone demethylase may be measured by the quotient of the IC50 value of the compound in inhibiting the activity of the second histone demethylase over the IC50 value of the compound in inhibiting the activity of the first histone demethylase.
  • the selectivity of a compound described herein in modulating the activity of a first histone demethylase over a second histone demethylase may also be measured by the quotient of the K d value of an adduct of the compound and the second histone demethylase over the K d value of an adduct of the compound and the first histone demethylase.
  • the histone demethylase is a KDM.
  • the KDM is KDM5.
  • the selectivity is at least about l-fold, at least about 2-fold, at least about 3 -fold, at least about 5- fold, at least about lO-fold, at least about 30-fold, at least about 50-fold, at least about lOO-fold, at least about 300-fold, at least about 500-fold, at least about 1, 000-fold, at least about 3,000- fold, at least about 5,000-fold, at least about 10, 000-fold, at least about 30,000-fold, at least about 50,000-fold, or at least about 100, 000-fold.
  • the compounds described herein may be useful in treating and/or preventing diseases associated with aberrant activity of a histone demethylase.
  • the aberrant activity is increased activity.
  • the aberrant activity is undesired activity.
  • the aberrant activity is abnormal activity.
  • the histone demethylase is a KDM.
  • the KDM is KDM5. It is known in the art that histone demethylases are implicated in a wide range of diseases and conditions, such as proliferative diseases. Therefore, the compounds described herein are expected to be useful in treating and/or preventing diseases.
  • the disease are proliferative diseases.
  • the disease are cardiovascular disease.
  • compositions comprising a compound described herein and optionally a pharmaceutically acceptable excipient.
  • a compound described herein is a compound of Formulae (I), (II), or a
  • the compound described herein is provided in an effective amount in the pharmaceutical composition.
  • the effective amount is a therapeutically effective amount.
  • the effective amount is a
  • a therapeutically effective amount is an amount effective for inhibiting the aberrant activity of a histone demethylase. In certain embodiments, a therapeutically effective amount is an amount effective for inhibiting the aberrant activity of KDM5 and treating a disease. In certain embodiments, a prophylactically effective amount is an amount effective for inhibiting the aberrant activity of a histone demethylase. In certain embodiments, a prophylactically effective amount is an amount effective for preventing or keeping a subject in need thereof in remission of a disease. In certain embodiments, a prophylactically effective amount is an amount effective for inhibiting the aberrant activity of KDM5, and preventing or keeping a subject in need thereof in remission of a disease.
  • the histone demethylase is a KDM.
  • the KDM is KDM5.
  • a therapeutically effective amount is an amount effective for treating a disease.
  • the disease is a disease associated with aberrant activity of KDM5.
  • the disease is a proliferative disease.
  • the disease is a cardiovascular disease.
  • the effective amount is an amount effective for inhibiting the activity of a histone demethylase by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 98%.
  • the effective amount is an amount effective for inhibiting the activity of a histone demethylase by not more than 10%, not more than 20%, not more than 30%, not more than 40%, not more than 50%, not more than 60%, not more than 70%, not more than 80%, not more than 90%, not more than 95%, or not more than 98%. In certain embodiments, the effective amount is an amount effective for inhibiting the activity of a KDM by not more than 10%, not more than 20%, not more than 30%, not more than 40%, not more than 50%, not more than 60%, not more than 70%, not more than 80%, not more than 90%, not more than 95%, or not more than 98%.
  • the histone demethylase is a KDM. In certain embodiments, the KDM is KDM5.
  • the subject is an animal.
  • the animal may be of either sex and may be at any stage of development.
  • the subject described herein is a human.
  • the subject is a non-human animal.
  • the subject is a mammal.
  • the subject is a non-human mammal.
  • the subject is a domesticated animal, such as a dog, cat, cow, pig, horse, sheep, or goat.
  • the subject is a companion animal, such as a dog or cat.
  • the subject is a livestock animal, such as a cow, pig, horse, sheep, or goat.
  • the subject is a zoo animal.
  • the subject is a research animal, such as a rodent, dog, pig, or non-human primate.
  • the rodent is a mouse.
  • the rodent is a rat.
  • the animal is a genetically engineered animal.
  • the animal is a transgenic animal.
  • the transgenic animal is a transgenic mouse.
  • the transgenic animal is a transgenic pig.
  • the subject is a fish or reptile.
  • the cell being contacted with a compound or composition described herein is in vitro. In certain embodiments, the cell being contacted with a compound or composition described herein is in vivo.
  • compositions described herein can be prepared by any method known in the art of pharmacology. In general, such preparatory methods include bringing the compound described herein (i.e ., the“active ingredient”) into association with a carrier or excipient, and/or one or more other accessory ingredients, and then, if necessary and/or desirable, shaping, and/or packaging the product into a desired single- or multi-dose unit.
  • compositions can be prepared, packaged, and/or sold in bulk, as a single unit dose, and/or as a plurality of single unit doses.
  • A“unit dose” is a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient.
  • the amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject and/or a convenient fraction of such a dosage, such as one- half or one-third of such a dosage.
  • compositions described herein will vary, depending upon the identity, size, and/or condition of the subject treated and further depending upon the route by which the composition is to be administered.
  • the composition may comprise between 0.1% and 100% (w/w) active ingredient.
  • compositions include inert diluents, dispersing and/or granulating agents, surface active agents and/or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, and/or oils. Excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavoring, and perfuming agents may also be present in the composition.
  • Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, powdered sugar, and mixtures thereof.
  • Exemplary granulating and/or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose, and wood products, natural sponge, cation-exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, and mixtures thereof.
  • crospovidone cross-linked poly(vinyl-pyrrolidone)
  • sodium carboxymethyl starch sodium starch glycolate
  • Exemplary surface active agents and/or emulsifiers include natural emulsifiers, colloidal clays, long chain amino acid derivatives, high molecular weight alcohols, carbomers, carrageenan, cellulosic derivatives, sorbitan fatty acid esters, poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic ® F-68, poloxamer P-188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, and/or mixtures thereof.
  • the natural emulsifier is acacia. In certain embodiments, the natural emulsifier is agar. In certain embodiments, the natural emulsifier is alginic acid. In certain embodiments, the natural emulsifier is sodium alginate. In certain embodiments, the natural emulsifier is tragacanth. In certain embodiments, the natural emulsifier is chondrux. In certain embodiments, the natural emulsifier is cholesterol. In certain embodiments, the natural emulsifier is xanthan. In certain embodiments, the natural emulsifier is pectin. In certain embodiments, the natural emulsifier is gelatin. In certain embodiments, the natural emulsifier is egg yolk.
  • the natural emulsifier is casein. In certain embodiments, the natural emulsifier is wool fat. In certain embodiments, the natural emulsifier is cholesterol. In certain embodiments, the natural emulsifier is wax. In certain embodiments, the natural emulsifier is lecithin. In certain embodiments, the colloidal clay is bentonite ( i.e ., aluminum silicate. In certain embodiments, the colloidal clay is Veegum ⁇ i.e., magnesium aluminum silicate). In certain embodiments, the high molecular weight alcohol is stearyl alcohol. In certain embodiments, the high molecular weight alcohol is cetyl alcohol. In certain embodiments, the high molecular weight alcohol is oleyl alcohol.
  • the high molecular weight alcohol is triacetin monostearate. In certain embodiments, the high molecular weight alcohol is ethylene glycol distearate. In certain embodiments, the high molecular weight alcohol is glyceryl monostearate. In certain embodiments, the high molecular weight alcohol is propylene glycol monostearate. In certain embodiments, the high molecular weight alcohol is polyvinyl alcohol. In certain embodiments, the carbomer is carboxy polymethylene. In certain embodiments, the carbomer is polyacrylic acid. In certain embodiments, the carbomer is acrylic acid polymer. In certain embodiments, the carbomer is carboxyvinyl polymer. In certain embodiments, the cellulosic derivative is carboxymethylcellulose sodium.
  • the cellulosic derivative is powdered cellulose. In certain embodiments, the cellulosic derivative is hydroxymethyl cellulose. In certain embodiments, the cellulosic derivative is hydroxypropyl cellulose. In certain embodiments, the cellulosic derivative is hydroxypropyl methylcellulose. In certain embodiments, the cellulosic derivative is
  • the sorbitan fatty acid ester is polyoxyethylene sorbitan monolaurate (Tween ® 20). In certain embodiments, the sorbitan fatty acid ester is
  • the sorbitan fatty acid ester is polyoxyethylene sorbitan monooleate (Tween ® 80). In certain embodiments, the sorbitan fatty acid ester is sorbitan monopalmitate (Span ® 40). In certain embodiments, the sorbitan fatty acid ester is sorbitan monostearate (Span ® 60). In certain embodiments, the sorbitan fatty acid ester is sorbitan tristearate (Span ® 65). In certain embodiments, the sorbitan fatty acid ester is glyceryl monooleate.
  • the sorbitan fatty acid ester is sorbitan monooleate (Span ® 80).
  • the polyoxyethylene ester is polyoxyethylene monostearate (Myrj ® 45).
  • the polyoxyethylene ester is polyoxyethylene hydrogenated castor oil.
  • the polyoxyethylene ester is polyethoxylated castor oil.
  • the polyoxyethylene ester is polyoxymethylene stearate.
  • the polyoxyethylene ester is Solutol ® .
  • the polyethylene glycol fatty acid ester is Cremophor ® .
  • the polyoxyethylene ether is polyoxyethylene lauryl ether (Brij ® 30).
  • Exemplary binding agents include starch, gelatin, sugars, natural and synthetic gums, magnesium aluminum silicate (Veegum ® ), and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol, and/or mixtures thereof.
  • the starch is cornstarch.
  • the starch is starch paste.
  • the sugar is sucrose.
  • the sugar is glucose.
  • the sugar is dextrose.
  • the sugar is dextrin.
  • the sugar is molasses.
  • the sugar is lactose. In certain embodiments, the sugar is lactitol. In certain embodiments, the sugar is mannitol. In certain embodiments, the synthetic gum is acacia. In certain embodiments, the synthetic gum is sodium alginate. In certain embodiments, the synthetic gum is extract of Irish moss. In certain embodiments, the synthetic gum is panwar gum. In certain embodiments, the synthetic gum is ghatti gum. In certain embodiments, the synthetic gum is mucilage of isapol husks. In certain embodiments, the synthetic gum is
  • the synthetic gum is methylcellulose. In certain embodiments, the synthetic gum is ethylcellulose. In certain embodiments, the synthetic gum is hydroxyethylcellulose. In certain embodiments, the synthetic gum is hydroxypropyl cellulose. In certain embodiments, the synthetic gum is hydroxypropyl methylcellulose. In certain embodiments,
  • the synthetic gum is microcrystalline cellulose. In certain embodiments, the synthetic gum is cellulose acetate. In certain embodiments, the synthetic gum is polyvinyl pyrrolidone).
  • Exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, antiprotozoan preservatives, alcohol preservatives, acidic preservatives, and other preservatives.
  • the preservative is an antioxidant.
  • the preservative is a chelating agent.
  • antioxidants include alpha tocopherol, ascorbic acid, acorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.
  • Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and salts and hydrates thereof, citric acid and salts and hydrates thereof, fumaric acid and salts and hydrates thereof, malic acid and salts and hydrates thereof, phosphoric acid and salts and hydrates thereof, and tartaric acid and salts and hydrates thereof.
  • EDTA ethylenediaminetetraacetic acid
  • Exemplary antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.
  • the EDTA salt is sodium edetate.
  • the EDTA salt is disodium edetate.
  • the EDTA salt is trisodium edetate.
  • the EDTA salt is calcium disodium edetate.
  • the EDTA salt is dipotassium edetate.
  • Exemplary antifungal preservatives include butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.
  • the citric acid is citric acid monohydrate.
  • Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol.
  • Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E, beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid.
  • preservatives include tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisol (BHA), butylated hydroxytoluened (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant ® Plus, Phenonip ® ,
  • Exemplary buffering agents include citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic sa
  • Exemplary lubricating agents include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and mixtures thereof.
  • Exemplary natural oils include almond, apricot kernel, avocado, babassu, bergamot, black current seed, borage, cade, camomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, com, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macademia nut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sasquana, savoury
  • Exemplary synthetic oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and mixtures thereof.
  • Liquid dosage forms for oral and parenteral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may comprise inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, dimethylformamide, oils, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol,
  • the oral compositions can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • the conjugates described herein are mixed with solubilizing agents such as Cremophor ® , alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and mixtures thereof.
  • the oil is cottonseed oil.
  • the oil is groundnut oil.
  • the oil is corn oil.
  • the oil is germ oil.
  • the oil is olive oil.
  • the oil is castor oil.
  • the oil is sesame oil.
  • Injectable preparations for example, sterile injectable aqueous or oleaginous
  • the sterile injectable preparation can be a sterile injectable solution, suspension, or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in l,3-butanediol.
  • acceptable vehicles and solvents that can be employed are water, Ringer’s solution, U.S.P., and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or di-glycerides.
  • fatty acids such as oleic acid are used in the preparation of injectables.
  • the injectable formulations can be sterilized, for example, by filtration through a bacterial -retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • compositions for rectal or vaginal administration are typically suppositories which can be prepared by mixing the conjugates described herein with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol, or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active ingredient.
  • suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol, or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active ingredient.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active ingredient is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or (a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders such as, for example, carboxymethylcellulose, alginates, gelatin,
  • the dosage form may include a buffering agent.
  • Solid compositions of a similar type can be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the art of pharmacology. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or in a certain part of the intestinal tract, optionally, in a delayed manner.
  • encapsulating compositions which can be used include polymeric substances and waxes.
  • Solid compositions of a similar type can be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the active ingredient can be in a micro-encapsulated form with one or more excipients as noted above.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings, and other coatings well known in the pharmaceutical formulating art.
  • the active ingredient can be admixed with at least one inert diluent such as sucrose, lactose, or starch.
  • Such dosage forms may comprise, as is normal practice, additional substances other than inert diluents.
  • the formulation comprises tableting lubricants.
  • the formulation comprises other tableting aids.
  • the formulation comprises magnesium stearate. In certain embodiments, the formulation comprises microcrystalline cellulose.
  • the dosage forms may comprise buffering agents. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of encapsulating agents which can be used include polymeric substances and waxes.
  • Dosage forms for topical and/or transdermal administration of a compound described herein may include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, and/or patches.
  • the active ingredient is admixed under sterile conditions with a pharmaceutically acceptable carrier or excipient and/or any needed preservatives and/or buffers as can be required.
  • the present disclosure contemplates the use of transdermal patches, which often have the added advantage of providing controlled delivery of an active ingredient to the body.
  • Such dosage forms can be prepared, for example, by dissolving and/or dispensing the active ingredient in the proper medium.
  • the rate can be controlled by either providing a rate controlling membrane and/or by dispersing the active ingredient in a polymer matrix and/or gel.
  • Suitable devices for use in delivering intradermal pharmaceutical compositions described herein include short needle devices.
  • Intradermal compositions can be administered by devices which limit the effective penetration length of a needle into the skin.
  • conventional syringes can be used in the classical mantoux method of intradermal administration.
  • Jet injection devices which deliver liquid formulations to the dermis via a liquid jet injector and/or via a needle which pierces the stratum comeum and produces a jet which reaches the dermis are suitable.
  • Ballistic powder/particle delivery devices which use compressed gas to accelerate the compound in powder form through the outer layers of the skin to the dermis are suitable.
  • Formulations suitable for topical administration include, but are not limited to, liquid and/or semi-liquid preparations such as liniments, lotions, oil-in-water and/or water-in-oil emulsions such as creams, ointments, and/or pastes, and/or solutions and/or suspensions.
  • liquid and/or semi-liquid preparations such as liniments, lotions, oil-in-water and/or water-in-oil emulsions such as creams, ointments, and/or pastes, and/or solutions and/or suspensions.
  • Topically administrable formulations may, for example, comprise from about 1% to about 10% (w/w) active ingredient, although the concentration of the active ingredient can be as high as the solubility limit of the active ingredient in the solvent.
  • Formulations for topical administration may further comprise one or more of the additional ingredients described herein.
  • a pharmaceutical composition described herein can be prepared, packaged, and/or sold in a formulation suitable for pulmonary administration via the buccal cavity.
  • a formulation may comprise dry particles which comprise the active ingredient and which have a diameter in the range from about 0.5 to about 7 nanometers, or from about 1 to about 6 nanometers.
  • Such compositions are conveniently in the form of dry powders for administration using a device comprising a dry powder reservoir to which a stream of propellant can be directed to disperse the powder and/or using a self-propelling solvent/powder dispensing container such as a device comprising the active ingredient dissolved and/or suspended in a low-boiling propellant in a sealed container.
  • Such powders comprise particles wherein at least 98% of the particles by weight have a diameter greater than 0.5 nanometers and at least 95% of the particles by number have a diameter less than 7 nanometers. Alternatively, at least 95% of the particles by weight have a diameter greater than 1 nanometer and at least 90% of the particles by number have a diameter less than 6 nanometers.
  • Dry powder compositions may include a solid fine powder diluent such as sugar and are conveniently provided in a unit dose form.
  • Low boiling propellants generally include liquid propellants having a boiling point of below 65 °F at atmospheric pressure.
  • the propellant may constitute 50 to 99.9% (w/w) of the composition, and the active ingredient may constitute 0.1 to 20% (w/w) of the composition.
  • the propellant may further comprise additional ingredients such as a liquid non ionic and/or solid anionic surfactant and/or a solid diluent (which may have a particle size of the same order as particles comprising the active ingredient).
  • compositions described herein formulated for pulmonary delivery may provide the active ingredient in the form of droplets of a solution and/or suspension.
  • Such formulations can be prepared, packaged, and/or sold as aqueous and/or dilute alcoholic solutions and/or suspensions, optionally sterile, comprising the active ingredient, and may conveniently be administered using any nebulization and/or atomization device.
  • Such formulations may further comprise one or more additional ingredients including, but not limited to, a flavoring agent such as saccharin sodium, a volatile oil, a buffering agent, a surface active agent, and/or a preservative such as methylhydroxybenzoate.
  • the droplets provided by this route of administration may have an average diameter in the range from about 0.1 to about 200 nanometers.
  • Formulations described herein as being useful for pulmonary delivery are useful for intranasal delivery of a pharmaceutical composition described herein.
  • Another formulation suitable for intranasal administration is a coarse powder comprising the active ingredient and having an average particle from about 0.2 to 500 micrometers. Such a formulation is
  • Formulations for nasal administration may, for example, comprise from about as little as 0.1% (w/w) to as much as 100% (w/w) of the active ingredient, and may comprise one or more of the additional ingredients described herein.
  • a pharmaceutical composition described herein can be prepared, packaged, and/or sold in a formulation for buccal administration. Such formulations may, for example, be in the form of tablets and/or lozenges made using
  • formulations for buccal administration may comprise a powder and/or an aerosolized and/or atomized solution and/or suspension comprising the active ingredient.
  • Such powdered, aerosolized, and/or aerosolized formulations, when dispersed, may have an average particle and/or droplet size in the range from about 0.1 to about 200 nanometers, and may further comprise one or more of the additional ingredients described herein.
  • a pharmaceutical composition described herein can be prepared, packaged, and/or sold in a formulation for ophthalmic administration.
  • Such formulations may, for example, be in the form of eye drops including, for example, a 0.1-1.0% (w/w) solution and/or suspension of the active ingredient in an aqueous or oily liquid carrier or excipient. Such drops may further comprise buffering agents, salts, and/or one or more other of the additional ingredients described herein.
  • Other opthalmically-administrable formulations which are useful include those which comprise the active ingredient in microcrystalline form and/or in a liposomal preparation. Ear drops and/or eye drops are also contemplated as being within the scope of this disclosure.
  • compositions are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and/or perform such modification with ordinary experimentation.
  • compositions described herein are typically formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the compositions described herein will be decided by a physician within the scope of sound medical judgment.
  • the specific therapeutically effective dose level for any particular subject or organism will depend upon a variety of factors including the disease being treated and the severity of the disorder; the activity of the specific active ingredient employed; the specific composition employed; the age, body weight, general health, sex, and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific active ingredient employed; the duration of the treatment; drugs used in combination or coincidental with the specific active ingredient employed; and like factors well known in the medical arts.
  • the compounds and compositions provided herein can be administered by any route, including enteral, parenteral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal, topical (as by powders, ointments, creams, and/or drops), mucosal, nasal, bucal, sublingual; by intratracheal instillation, bronchial instillation, and/or inhalation; and/or as an oral spray, nasal spray, and/or aerosol.
  • the enteral administration is oral administration.
  • Specifically contemplated routes are oral administration, intravenous administration, regional administration via blood and/or lymph supply, and/or direct
  • the most appropriate route of administration will depend upon a variety of factors including the nature of the agent, including but not limited to, stability in the environment of the gastrointestinal tract, and/or the condition of the subject, including but not limited to, whether the subject is able to tolerate oral administration.
  • the compound or pharmaceutical composition described herein is suitable for topical administration to the eye of a subject.
  • the intravenous administration is systemic intravenous injection.
  • the exact amount of a compound required to achieve an effective amount will vary from subject to subject, depending, for example, on species, age, and general condition of a subject, severity of the side effects or disorder, identity of the particular compound, mode of
  • any two doses of the multiple doses include different or substantially the same amounts of a compound described herein.
  • the frequency of administering the multiple doses to the subject or applying the multiple doses to the biological sample is three doses a day, two doses a day, one dose a day, one dose every other day, one dose every third day, one dose every week, one dose every two weeks, one dose every three weeks, or one dose every four weeks.
  • the frequency of administering the multiple doses to the subject or applying the multiple doses to the biological sample is one dose per day. In certain embodiments, the frequency of administering the multiple doses to the subject or applying the multiple doses to the biological sample is two doses per day. In certain embodiments, the frequency of administering the multiple doses to the subject or applying the multiple doses to the biological sample is three doses per day.
  • the duration between the first dose and last dose of the multiple doses is one day, two days, four days, one week, two weeks, three weeks, one month, two months, three months, four months, six months, nine months, one year, two years, three years, four years, five years, seven years, ten years, fifteen years, twenty years, or the lifetime of the subject, tissue, or cell.
  • the duration between the first dose and last dose of the multiple doses is three months, six months, or one year.
  • the duration between the first dose and last dose of the multiple doses is the lifetime of the subject, tissue, or cell.
  • a dose described herein includes independently between 0.1 pg and 1 pg, between 0.001 mg and 0.01 mg, between 0.01 mg and 0.1 mg, between 0.1 mg and 1 mg, between 1 mg and 3 mg, between 3 mg and 10 mg, between 10 mg and 30 mg, between 30 mg and 100 mg, between 100 mg and 300 mg, between 300 mg and 1,000 mg, or between 1 g and 10 g, inclusive, of a compound described herein.
  • a dose described herein includes independently between 1 mg and 3 mg, inclusive, of a compound described herein.
  • a dose described herein includes independently between 3 mg and 10 mg, inclusive, of a compound described herein.
  • a dose described herein includes independently between 10 mg and 30 mg, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 30 mg and 100 mg, inclusive, of a compound described herein.
  • the biological sample is a cell. In certain embodiments, the biological sample is a tissue. In certain embodiments, the dose is a single dose. In certain embodiments, the dose is a single oral dose. In certain embodiments, the dose is multiple doses.
  • Dose ranges as described herein provide guidance for the administration of provided pharmaceutical compositions to an adult.
  • the amount to be administered to, for example, a child or an adolescent can be determined by a medical practitioner or person skilled in the art and can be lower or the same as that administered to an adult.
  • a compound or composition, as described herein, can be administered in combination with one or more additional pharmaceutical agents.
  • the additional pharmaceutical agent is a therapeutically active agent.
  • the additional pharmaceutical agent is a prophylactically active agent.
  • the compounds or compositions can be administered in combination with additional pharmaceutical agents that improve their activity in treating a disease in a subject in need thereof, in preventing a disease in a subject in need thereof, in inhibiting the activity of a histone demethylase in a subject, or biological sample, improve bioavailability, improve safety, reduce drug resistance, reduce and/or modify metabolism, inhibit excretion, and/or modify distribution in a subject, biological sample.
  • activity is efficacy.
  • activity is potency.
  • a pharmaceutical composition described herein including a compound described herein and an additional pharmaceutical agent shows a synergistic effect that is absent in a pharmaceutical composition including one of the compound and the additional pharmaceutical agent, but not both.
  • the histone demethylase is a KDM.
  • the KDM is KDM5.
  • the biological sample is a cell. In certain embodiments, the biological sample is a tissue.
  • the compound or composition can be administered concurrently with, prior to, or subsequent to one or more additional pharmaceutical agents, which may be useful as.
  • the compound or composition can be administered in a combination therapy.
  • Pharmaceutical agents include therapeutically active agents.
  • Pharmaceutical agents also include prophylactically active agents.
  • Pharmaceutical agents include small organic molecules such as drug compounds, peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNAs, RNAs, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and cells.
  • the additional pharmaceutical agent is a
  • the disease is a proliferative disease.
  • the disease is a cardiovascular disease.
  • Each additional pharmaceutical agent may be administered at a dose and/or on a time schedule determined for that pharmaceutical agent.
  • the drug compounds is a compound approved for human or veterinary use by the U.S. Food and Drug Administration as provided in the Code of Federal Regulations (CFR),
  • the additional pharmaceutical agents may also be administered together with each other and/or with the compound or composition described herein in a single dose or administered separately in different doses.
  • the particular combination to employ in a regimen will take into account compatibility of the compound described herein with the additional pharmaceutical agent(s) and/or the desired therapeutic and/or prophylactic effect to be achieved.
  • the additional pharmaceutical agents include, but are not limited to, anti-proliferative agents, anti-cancer agents, anti-angiogenesis agents, anti-inflammatory agents, and
  • the additional pharmaceutical agent is an anti-proliferative agent.
  • the anti-proliferative agent is an anti cancer agent.
  • the additional pharmaceutical agent is an anti-leukemia agent.
  • the additional pharmaceutical agent is ABITREXATE
  • PURINETHOL mercaptopurine
  • PURIXAN mercaptopurine
  • Rubidomycin daunorubicin hydrochloride
  • SPRYCEL dasatinib
  • SYNRIBO omacetaxine mepesuccinate
  • TARABINE PFS cytarabine
  • TASIGNA nolotinib
  • TREANDA bendamustine hydrochloride
  • TRISENOX arsenic trioxide
  • VINCASAR PFS vincristine sulfate
  • ZYDELIG idelalisib
  • the additional pharmaceutical agent is an anti lymphoma agent.
  • the additional pharmaceutical agent is ABITREXATE (methotrexate), ABVD, ABVE, ABVE-PC, ADCETRIS (brentuximab vedotin), ADRIAMYCIN PFS (doxorubicin hydrochloride), ADRIAMYCIN RDF (doxorubicin hydrochloride),
  • AMBOCHLORIN chlorambucil
  • AMBOCLORIN chlorambucil
  • ARRANON nelarabine
  • BELEODAQ belinostat
  • BEXXAR tositumomab and iodine 1 131 tositumomab
  • BICNET carmustine
  • BLENOXANE bleomycin
  • CARMUBRIS carmustine
  • CHOP CLAFEN (cyclophosphamide)
  • COPP COPP-ABV
  • CVP CYTOXAN
  • CYT liposomal cytarabine
  • DTIC-DOME diacarbazine
  • EPOCH FOLEX (methotrexate), FOLEX PFS (methotrexate), FOLOTYN (pralatrexate), HYPER- CVAD, ICE, IMBRUVICA (ibrutinib), INTRON A (chlorambucil), AM
  • MATULANE procarbazine hydrochloride
  • METHOTREXATE LPF metalhotrexate
  • MEXATE metalhotrexate
  • MEXATE-AQ metalhotrexate
  • MUSTARGEN mechlorethamine hydrochloride
  • NEOSAR cyclophosphamide
  • OEPA ONTAK (denileukin diftitox), OPPA, R-CHOP, REVLIMID (lenalidomide), RITUXAN (rituximab), STANFORD V, TREANDA (bendamustine hydrochloride), VAMP, VELBAN (vinblastine sulfate), VELCADE (bortezomib), VELSAR (vinblastine sulfate), VINCASAR PFS (vincristine sulfate), ZEVALIN (ibritumomab tiuxetan), ZOLINZA (vor
  • the additional pharmaceutical agent is NEOSAR (cyclophosphamide), FLUDARA (fludarabine), LEUSTATIN (cladribine), or a combination thereof.
  • the additional pharmaceutical agent is
  • ABITREXATE metalhotrexate
  • ABRAXANE paclitaxel albumin-stabilized nanoparticle formulation
  • ADRUCIL fluorouracil
  • AFINITOR everolimus
  • AFINITOR DISPERZ everolimus
  • ALDARA ABITREXATE
  • hydrochloride liposome DOXORUBICIN HYDROCHLORIDE, DOX-SL (doxorubicin hydrochloride liposome), DTIC-DOME (dacarbazine), EFUDEX (fluorouracil), ELLENCE (epirubicin hydrochloride), ELOXATIN (oxaliplatin), ERBITUX (cetuximab), ERIVEDGE (vismodegib), ETOPOPHOS (etoposide phosphate), EVACET (doxorubicin hydrochloride liposome), FARESTON (toremifene), FASLODEX (fulvestrant), FEC, FEMARA (letrozole), FLUOROPLEX (fluorouracil), FOLEX (methotrexate), FOLEX PFS (methotrexate), FOLFIRI , FOLFIRI-BEVACIZUMAB, FOLFIRI-CETUXIMAB, FOLFIRINOX, FOLFOX, F
  • GEMCITABINE-CISPLATIN GEMCIT AB INE- OX ALIPLATIN , GEMZAR (gemcitabine hydrochloride), GILOTRIF (afatinib dimaleate), GLEEVEC (imatinib mesylate), GLIADEL (carmustine implant), GLIADEL WAFER (carmustine implant), HERCEPTIN (trastuzumab), HYCAMTIN (topotecan hydrochloride), IFEX (ifosfamide), IFOSFAMIDUM (ifosfamide), INLYTA (axitinib), INTRON A (recombinant interferon alfa-2b), IRESSA (gefitinib),
  • IXEMPRA ixabepilone
  • JAKAFI ruxolitinib phosphate
  • JEVTANA cabazitaxel
  • KADCYLA ado-trastuzumab emtansine
  • KEYTRUDA pembrolizumab
  • ZALTRAP ziv-aflibercept
  • ZELBORAF vemurafenib
  • ZOLADEX goserelin acetate
  • ZOMETA zoledronic acid
  • ZYKADIA ceritinib
  • ZYTIGA abiraterone acetate
  • the proteasome inhibitor is bortezomib (Velcade). In certain embodiments, the mTOR inhibitor is rapamycin. In certain embodiments, the mTOR inhibitor is temsirolimus (CCI-779). In certain embodiments, the mTOR inhibitor is everolimus (RAD-001). In certain embodiments, the mTOR inhibitor is ridaforolimus. In certain embodiments, the mTOR inhibitor is AP23573 (Ariad). In certain embodiments, the mTOR inhibitor is AZD8055 (AstraZeneca). In certain embodiments, the mTOR inhibitor is BEZ235 (Novartis). In certain embodiments, the mTOR inhibitor is BGT226 (Norvartis).
  • the mTOR inhibitor is XL765 (Sanofi Aventis). In certain embodiments, the mTOR inhibitor is PF-4691502 (Pfizer). In certain embodiments, the mTOR inhibitor is GDC0980 (Genetech). In certain embodiments, the mTOR inhibitor is SF1126 (Semafoe). In certain embodiments, the mTOR inhibitor is OSI-027 (OSI). In certain embodiments,
  • the additional pharmaceutical agent is ibrutinib. In certain embodiments, the additional pharmaceutical agent is a protein kinase inhibitor. In certain embodiments, the additional protein kinase inhibitor is a tyrosine protein kinase inhibitor. In certain embodiments, the additional pharmaceutical agent is a binder or inhibitor of a histone demethylase. In certain embodiments, the histone demethylase is a KDM. In certain embodiments, the KDM is KDM5.
  • the additional pharmaceutical agent is a binder or inhibitor of a KDM.
  • the additional pharmaceutical agent is a binder or inhibitor of KDM5. In certain embodiments, the additional pharmaceutical agent is a binder or inhibitor of Bruton’s tyrosine kinase (BTK). In certain embodiments, the additional pharmaceutical agent is selected from the group consisting of epigenetic or transcriptional modulators, antimitotic drugs, hormone receptor modulators, Hsp90 inhibitors, glucocorticoids, all -trans retinoic acids, and other agents that promote differentiation. In certain embodiments, the compounds described herein or pharmaceutical compositions can be administered in combination with an anti-cancer therapy including, but not limited to, surgery, radiation therapy, transplantation, immunotherapy, and chemotherapy. In certain embodiments, the transplantation is stem cell transplantation.
  • the transplantation is bone marrow transplantation.
  • the transcriptional modulator is a DNA methyltransferase inhibitor.
  • the transcriptional modulator is histone deacetylase inhibitors (HD AC inhibitors).
  • the transcriptional modulator is a lysine methyltransferase inhibitors.
  • the antimitotic drug is a taxanes.
  • the antimitotic drug is a vinca alkaloids.
  • the hormone receptor modulator is an estrogen receptor modulators.
  • the hormone receptor modulator is an androgen receptor modulators.
  • the cell signaling pathway inhibitor is a tyrosine protein kinase inhibitors.
  • the modulator of protein stability is a proteasome inhibitors.
  • kits are pharmaceutical packs.
  • the kits provided may comprise a pharmaceutical composition or compound described herein and a container.
  • the container is a vial.
  • the container is an ampule.
  • the container is bottle.
  • the container is a syringe.
  • the container is a dispenser package.
  • the container is another suitable container.
  • provided kits may optionally further include a second container comprising a pharmaceutical excipient for dilution or suspension of a pharmaceutical composition or compound described herein.
  • the pharmaceutical composition or compound described herein provided in the first container and the second container are combined to form one unit dosage form.
  • kits including a first container comprising a compound or pharmaceutical composition described herein.
  • the kits are useful for treating a disease in a subject in need thereof.
  • the kits are useful for preventing a disease in a subject in need thereof.
  • the kits are useful for inhibiting the activity of a histone demethylase in a subject, or biological sample.
  • the disease is a proliferative disease.
  • the disease is a cardiovascular disease.
  • the histone demethylase is a KDM.
  • the KDM is KDM5.
  • the biological sample is a tissue.
  • the biological sample is a cell.
  • the activity is aberrant activity.
  • the activity is increased activity.
  • kits described herein further includes instructions for using the compound or pharmaceutical composition included in the kit.
  • a kit described herein may also include information as required by a regulatory agency such as the U.S. Food and Drug
  • kits and instructions provide for treating a disease in a subject in need thereof. In certain embodiments, the kits and instructions provide for preventing a disease in a subject in need thereof. In certain embodiments, the kits and kits and
  • kits described herein may include one or more additional pharmaceutical agents described herein as a separate composition.
  • the disease is a proliferative disease.
  • the disease is a cardiovascular disease.
  • the histone demethylase is a KDM.
  • the KDM is KDM5.
  • the biological sample is a tissue.
  • the biological sample is a cell.
  • the activity is aberrant activity.
  • the activity is increased activity.
  • the present disclosure provides methods of modulating the activity of a histone demethylase.
  • the present disclosure provides methods of modulating the activity of a histone demethylase in a subject, or biological sample.
  • the activity of a histone demethylase is increased.
  • the activity of a histone demethylase is decreased.
  • the aberrant activity is increased activity.
  • the aberrant activity is decreased activity.
  • the biological sample is a cell.
  • the biological sample is a tissue.
  • the present disclosure also provides methods for the treatment of a wide range of diseases in a subject in need thereof.
  • the disease is a disease associated with the aberrant activity of a histone demethylase. In certain embodiments, the disease is a proliferative disease.
  • the present disclosure provides methods for the treatment and/or prevention of a proliferative disease.
  • the proliferative disease is cancer.
  • the cancer is In certain embodiments, the cancer is carcinoma.
  • the cancer is lung cancer. In certain embodiments, the cancer is breast cancer. In certain embodiments, the cancer is liver cancer. In certain embodiments, the cancer is pancreatic cancer.
  • the cancer is gastric cancer. In certain embodiments, the cancer is ovarian cancer. In certain embodiments, the cancer is colon cancer. In certain embodiments, the cancer is colorectal cancer. In certain embodiments, the disease is a cardiovascular disease.
  • the present disclosure also provides a compound of Formulae (I), (II), or a
  • the present disclosure provides a compound of Formulae (I), (II), or a pharmaceutically acceptable salt, or composition thereof, for use in the treatment of diseases, such as proliferative diseases and/or cardiovascular diseases, in a subject in need thereof.
  • the present disclosure also provides uses of a compound of Formulae (I), (II), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate,
  • the present disclosure provides uses of a compound of Formulae (I), (II), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of diseases, such as proliferative diseases and/or cardiovascular diseases, in a subject in need thereof.
  • the present disclosure provides uses of a compound of Formulae (I), (II), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of diseases, such as proliferative diseases and/or
  • the present disclosure provides methods of modulating the activity of a histone demethylase in a subject, or biological sample. In another aspect, the present disclosure provides methods of modulating the activity of a histone demethylase in a subject, or biological sample. In certain embodiments, provided are methods of inhibiting the activity of a histone demethylase in a subject. In certain embodiments, provided are methods of inhibiting the activity of a histone demethylase in a subject. In certain embodiments, provided are methods of inhibiting the activity of a histone demethylase in a cell.
  • the compounds described herein may exhibit histone demethylase inhibitory activity; the ability to inhibit a KDM; the ability to inhibit KDM5, without inhibiting another KDM; a therapeutic effect and/or preventative effect in the treatment of cancers; a therapeutic effect and/or preventative effect in the treatment of proliferative diseases and/or cardiovascular diseases; and/or a therapeutic profile that is superior to existing chemotherapeutic agents, or agents for treating other diseases.
  • the therapeutic profile has a superior optimum safety. In certain embodiments, the therapeutic profile has a superior curative effect. In certain embodiments, the histone
  • demethylase is a KDM.
  • the KDM is KDM5.
  • the biological sample is a cell.
  • the biological sample is a tissue.
  • the activity of a histone demethylase in a subject or cell is decreased by a method described herein by at least about 1%, at least about 3%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%.
  • the activity of a histone demethylase in a subject or cell is selectively inhibited by the method. In some embodiments, the activity of a histone demethylase in a subject or cell is selectively decreased by the method. In some embodiments, the activity of KDM5 in a subject or cell is selectively decreased, compared to another KDM by the method. In some embodiments, the activity of one KDM in a subject or cell is selectively decreased, compared to another KDM by the method. In certain embodiments, the histone demethylase is a KDM. In certain embodiments, the KDM is KDM5. In certain embodiments, the biological sample is a cell. In certain embodiments,
  • the biological sample is a tissue.
  • the compounds described herein are able to bind the histone demethylase being inhibited.
  • a compound described herein is able to bind the histone demethylase.
  • the compound described herein is able to covalently bind a KDM.
  • the compound described herein is able to covalently bind KDM5.
  • the compounds as described herein covalently modify the histone demethylase.
  • the present disclosure provides methods of inhibiting the activity of a histone demethylase in a subject, the methods comprising administering to the subject an effective amount of a compound, or pharmaceutical composition thereof, as described herein.
  • the present disclosure provides methods of inhibiting the activity of a histone demethylase in a biological sample, the methods comprising contacting the biological sample with an effective amount of a compound, or pharmaceutical composition thereof, as described herein.
  • the present disclosure provides methods of inhibiting the activity of a histone demethylase in a tissue or cell, the methods comprising contacting the tissue or cell with an effective amount of a compound, or pharmaceutical composition thereof, as described herein.
  • the histone demethylase is a KDM.
  • the KDM is KDM5.
  • the present disclosure provides methods of inhibiting the activity of a histone demethylase in a cell, the methods comprising contacting the cell with an effective amount of a compound, or pharmaceutical composition thereof, as described herein.
  • the histone demethylase is a KDM.
  • the KDM is KDM5.
  • the subject being treated is a mammal.
  • the subject is a human.
  • the subject is a domesticated animal, such as a dog, cat, cow, pig, horse, sheep, or goat.
  • the subject is a companion animal, such as a dog or cat.
  • the subject is a livestock animal, such as a cow, pig, horse, sheep, or goat.
  • the subject is a zoo animal.
  • the subject is a research animal such as a rodent, dog, or non-human primate.
  • the subject is a non-human transgenic animal such as a transgenic mouse or transgenic pig.
  • the biological sample being contacted with the compound or composition is breast tissue, bone marrow, lymph node, lymph tissue, spleen, or blood.
  • the biological sample being contacted with the compound or composition is a tumor or cancerous tissue.
  • the biological sample being contacted with the compound or composition is serum, cerebrospinal fluid, interstitial fluid, mucous, tears, sweat, pus, biopsied tissue, nipple aspirates, milk, vaginal fluid, saliva, swabs (such as buccal swabs), or any material containing biomolecules that is derived from a first biological sample.
  • the biopsied tissue is obtained by a surgical biopsy.
  • the biopsied tissue is obtained by a needle biopsy.
  • the cell or tissue being contacted with the compound or composition is present in vitro. In certain embodiments, the cell or tissue being contacted with the compound or composition is present in vivo. In certain embodiments, the cell or tissue being contacted with the compound or composition is present ex vivo. In certain embodiments, the cell or tissue being contacted with the compound or composition is a malignant cell. In certain embodiments, the malignant cell is a malignant blood cell. In certain embodiments, the cell being contacted with the compound or composition is a malignant hematopoietic stem cell. In certain embodiments, the malignant hematopoietic stem cell is a malignant myeloid cell.
  • the malignant hematopoietic stem cell is malignant lymphoid cell.
  • the cell being contacted with the compound or composition is a malignant lymphocyte.
  • the malignant lymphocyte is a malignant T-cell.
  • the malignant lymphocyte is a malignant B-cell.
  • the cell being contacted with the compound or composition is a malignant white blood cell.
  • the cell being contacted with the compound or composition is a malignant neutrophil, malignant macrophage, or malignant plasma cell.
  • the cell being contacted with the compound or composition is a carcinoma cell.
  • the cell being contacted with the compound or composition is a breast carcinoma cell.
  • the cell being contacted with the compound or composition is a sarcoma cell.
  • the cell being contacted with the compound or composition is a sarcoma cell from breast tissue.
  • the disease to be treated or prevented using the compounds described herein may be associated with increased activity of a histone demethylase, such as a KDM.
  • the disease to be treated or prevented using the compounds described herein may be associated with the overexpression of a histone demethylase, such as a KDM.
  • the disease is a proliferative disease.
  • the disease is a cardiovascular disease.
  • the histone demethylase is a KDM.
  • the KDM is KDM5.
  • the disease to be treated or prevented using the compounds described herein may be associated with the overexpression of a histone demethylase, such as a KDM.
  • a disease may be associated with the aberrant activity of a histone demethylase, such as a KDM.
  • Aberrant activity of a histone demethylase, such as a KDM may be elevated and/or inappropriate or undesired activity of the histone demethylase.
  • the compounds described herein, and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, prodrugs, and compositions thereof may inhibit the activity of a histone demethylase and be useful in treating and/or preventing diseases.
  • the compounds described herein, and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, prodrugs, and compositions thereof may inhibit the activity of a CDK and be useful in treating and/or preventing diseases.
  • the compounds described herein, and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, prodrugs, and compositions thereof, may inhibit the activity of a histone
  • the disease is a proliferative disease. In certain embodiments, the disease is a cardiovascular disease.
  • the disease to be treated or prevented using the compounds described herein is cancer. All types of cancers disclosed herein or known in the art are contemplated as being within the scope of the present disclosure.
  • the disease is a proliferative disease.
  • the disease is a cardiovascular disease.
  • the proliferative disease is a hematological malignancy.
  • the proliferative disease is a blood cancer.
  • the proliferative disease is leukemia.
  • the proliferative disease is a carcinoma.
  • the proliferative disease is lymphoma.
  • the proliferative disease is T-cell lymphoma. In some embodiments, the proliferative disease is Burkitt’s lymphoma. In certain embodiments, the proliferative disease is a Hodgkin’s lymphoma. In certain embodiments, the proliferative disease is a non-Hodgkin’s lymphoma. In certain embodiments, the proliferative disease is multiple myeloma. In certain embodiments, the proliferative disease is melanoma. In certain embodiments, the proliferative disease is colorectal cancer. In certain embodiments, the proliferative disease is colon cancer. In certain embodiments, the proliferative disease is breast cancer.
  • the proliferative disease is recurring breast cancer. In certain embodiments, the proliferative disease is mutant breast cancer. In certain embodiments, the proliferative disease is HER2+ breast cancer. In certain embodiments, the proliferative disease is HER2- breast cancer. In certain embodiments, the proliferative disease is triple-negative breast cancer (TNBC). In certain embodiments, the proliferative disease is a bone cancer. In certain embodiments, the proliferative disease is osteosarcoma. In certain embodiments, the proliferative disease is Ewing’s sarcoma. In some embodiments, the proliferative disease is a brain cancer. In some embodiments, the proliferative disease is neuroblastoma.
  • the proliferative disease is a lung cancer. In some embodiments, the proliferative disease is small cell lung cancer (SCLC). In some embodiments, the proliferative disease is non-small cell lung cancer (NSCLC). In some embodiments, the proliferative disease is liver cancer. In some embodiments, the proliferative disease is pancreatic cancer. In some embodiments, the proliferative disease is gastric cancer. In some embodiments, the proliferative disease is bladder cancer. In some embodiments, the proliferative disease is prostate cancer. In some embodiments, the proliferative disease is ovarian cancer. In some embodiments, the proliferative disease is ovarian cancer. In some embodiments, the proliferative disease is ovarian cancer.
  • the proliferative disease is a benign neoplasm.
  • the proliferative disease is lung cancer, breast cancer, liver cancer, pancreatic cancer, gastric cancer, ovarian cancer, colon cancer, colorectal cancer, bladder cancer, or prostate cancer.
  • the proliferative disease is associated with angiogenesis. All types of angiogenesis disclosed herein or known in the art are contemplated as being within the scope of the present disclosure.
  • the disease to be treated or prevented using the compounds described herein is cardiovascular disease.
  • the cardiovascular disease is heart disease.
  • the cardiovascular disease is coronary heart disease.
  • the cardiovascular disease is stroke or cerebrovascular disease.
  • the cardiovascular disease is a congenital heart defect.
  • the cardiovascular disease is peripheral artery disease.
  • the cardiovascular disease is heart disease associated with atherosclerosis.
  • the cardiovascular disease is heart disease associated with atherosclerosis.
  • cardiovascular disease is ischemic heart disease. In certain embodiments, the cardiovascular disease is hypertensive heart disease. In certain embodiments, the cardiovascular disease is cardiac arrhythmia. In certain embodiments, the cardiovascular disease is heart failure, congenital heart disease. In certain embodiments, the cardiovascular disease is inflammatory heart disease. In certain embodiments, the cardiovascular disease is cardiomyopathy.
  • the histone demethylase is KDM.
  • the KDM is KDM5.
  • the KDM is KDM5A.
  • the KDM is KDM5B.
  • the KDM is KDM3.
  • the activity of the histone demethylase that is inhibited is aberrant activity of the histone demethylase.
  • the activity of the histone demethylase is increased activity of the histone demethylase.
  • the inhibition of the activity of the histone demethylase is irreversible.
  • the methods of inhibiting the activity of the histone demethylase include attaching a compound described herein to the histone demethylase.
  • the methods comprise covalently inhibiting a histone demethylase.
  • the present disclosure provides methods of inhibiting cell growth in a biological sample, or subject.
  • the histone demethylase is a KDM.
  • the KDM is KDM5.
  • the biological sample is a cell.
  • the biological sample is a tissue.
  • the methods described herein include administering to a subject or contacting a biological sample with an effective amount of a compound described herein, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof.
  • the methods described herein include
  • the biological sample is a cell or tissue.
  • the biological sample is a cell.
  • the biological sample is tissue.
  • the compound is contacted with a biological sample.
  • the compound is administered to a subject.
  • the compound is administered in combination with one or more additional pharmaceutical agents described herein.
  • the additional pharmaceutical agent may be an anti-proliferative agent.
  • the additional pharmaceutical agent is an anti-cancer agent.
  • the additional pharmaceutical agent may also be a kinase inhibitor.
  • the additional pharmaceutical agent is an inhibitor of histone demethylase. In certain embodiments, the additional pharmaceutical agent is an inhibitor of a KDM. In certain embodiments, the additional pharmaceutical agent includes an anti-cancer agent, anti-inflammatory agent, steroids, immunosuppressant, radiation therapy, or other agents. In certain embodiments, the additional pharmaceutical agent is an anti-proliferative agent. In certain embodiments, the additional pharmaceutical agent is a non-selective inhibitor of a histone demethylase. In certain
  • the additional pharmaceutical agent is an immunotherapy agent. In certain embodiments, the additional pharmaceutical agent is an immune checkpoint inhibitor. In certain embodiments, the anti-cancer agent is a chemotherapeutic. In certain embodiments, the immunotherapy agent is a PD1 inhibitor. In certain embodiments, the immunotherapy agent is a PDL1 inhibitor.
  • the additional pharmaceutical agent is a topoisomerase inhibitor, a MCL1 inhibitor, a BCL-2 inhibitor, a BCL-xL inhibitor, a BRD4 inhibitor, a BRCA1 inhibitor, BRCA2 inhibitor, HER1 inhibitor, HER2 inhibitor, a CDK9 inhibitor, a Jumonji histone demethylase inhibitor, or a DNA damage inducer.
  • the additional pharmaceutical agent is etoposide, obatoclax, navitoclax, JQ1, 4-(((5’-chloro-2’-(((lR,4R)-4- (((R)-l-methoxypropan-2-yl)amino)cyclohexyl)amino)-[2,4’-bipyridin]-6- yl)amino)methyl)tetrahydro-2H-pyran-4-carbonitrile, JIB04, or cisplatin.
  • JQ1 4-((5’-chloro-2’-(((lR,4R)-4- (((R)-l-methoxypropan-2-yl)amino)cyclohexyl)amino)-[2,4’-bipyridin]-6- yl)amino)methyl)tetrahydro-2H-pyran-4-carbonitrile, JIB04, or cisplatin.
  • chemotherapeutic agents include alkylating agents such as nitrogen mustards, ethylenimines, methylmelamines, alkyl sulfonates, nitrosuoureas, and triazenes; antimetabolites such as folic acid analogs, pyrimidine analogs, in particular fluorouracil and cytosine arabinoside, and purine analogs; natural products such as vinca alkaloids epi-podophyllotoxins, antibiotics, enzymes, and biological response modifiers; and miscellaneous products such as platinum coordination complexes, anthracenedione, substituted urea such as hydroxyurea, methyl hydrazine derivatives, and adrenocorticoid suppressant.
  • alkylating agents such as nitrogen mustards, ethylenimines, methylmelamines, alkyl sulfonates, nitrosuoureas, and triazenes
  • antimetabolites such as folic acid analogs,
  • chemotherapeutic agents also include anthracycline antibiotics, actinomycin D, plicamycin, puromycin, gramicidin D, paclitaxel, colchicine, cytochalasin B, emetine, maytansine, amsacrine, cisplatin, carboplatin, mitomycin, altretamine, cyclophosphamide, lomustine, and carmustine.
  • a pharmaceutical composition described herein further comprises a combination of the additional pharmaceutical agents described herein.
  • the compounds or compositions disclosed herein may synergistically augment inhibition of histone demethylase induced by the additional pharmaceutical agent(s) in the biological sample or subject.
  • the combination of the compounds or compositions disclosed herein and the additional pharmaceutical agent(s) may be useful in treating proliferative diseases and/or cardiovascular diseases resistant to a treatment using the additional pharmaceutical agent(s) without the compounds or compositions.
  • the activity of a histone demethylase is non-selectively inhibited by the compounds or pharmaceutical compositions described herein. In some embodiments, the activity of the histone demethylase being inhibited is selectively inhibited by the compounds or pharmaceutical compositions described herein, compared to the activity of a different protein. In certain embodiments, the activity of a histone demethylase is selectively inhibited by a compound or pharmaceutical composition described herein, compared to the activity of a different protein. In certain embodiments, the activity of KDM5 is selectively inhibited by a compound or pharmaceutical composition described herein, compared to the activity of another KDM. In certain embodiments, the KDM is KDM2/7.
  • the KDM is KDM3. In certain embodiments, the KDM is KDM4. In certain embodiments, the KDM is KDM6. In certain embodiments, the histone demethylase is a KDM. In certain embodiments, the KDM is KDM5.
  • the selectivity of a compound or pharmaceutical composition described herein in inhibiting the activity of a histone demethylase over a different histone demethylase may be measured by the quotient of the IC50 value of the compound or pharmaceutical composition in inhibiting the activity of the different histone demethylase over the IC50 value of the compound or pharmaceutical composition in inhibiting the activity of the histone demethylase.
  • the selectivity of a compound or pharmaceutical composition described herein for a histone demethylase over a different histone demethylase may also be measured by the quotient of the K d value of an adduct of the compound or pharmaceutical composition and the different protein over the K d value of an adduct of the compound or pharmaceutical composition and the histone demethylase.
  • the selectivity is at least 2-fold, at least 3-fold, at least 5- fold, at least lO-fold, at least 30-fold, at least 50-fold, at least lOO-fold, at least 300-fold, at least 500-fold, at least 1, 000-fold, at least 3,000-fold, at least 5,000-fold, at least 10, 000-fold, at least 30,000-fold, at least 50,000-fold, or at least 100, 000-fold.
  • the selectivity is not more than 100, 000-fold, not more than 10, 000-fold, not more than 1, 000-fold, not more than lOO-fold, not more than lO-fold, or not more than 2-fold. Combinations of the above- referenced range are also within the scope of the disclosure.
  • the histone demethylase is a KDM.
  • the KDM is KDM5.
  • a kit described herein includes a first container comprising a compound or pharmaceutical composition described herein.
  • a kit described herein is useful in treating and/or preventing a disease, such as a proliferative disease, cancer and/or cardiovascular disease, in a subject in need thereof, or inhibiting the activity of a histone demethylase in a subject, or biological sample.
  • a kit described herein is useful in treating and/or preventing a disease, such as a proliferative disease and/or cardiovascular disease), in a subject in need thereof.
  • the proliferative disease is cancer.
  • the cancer is carcinoma.
  • the cancer is lung cancer.
  • the cancer is breast cancer.
  • the cancer is liver cancer. In certain embodiments, the cancer is pancreatic cancer. In certain embodiments, the cancer is gastric cancer. In certain embodiments, the cancer is ovarian cancer. In certain embodiments, the cancer is colon cancer. In certain embodiments, the cancer is colorectal cancer. In certain embodiments, the cancer is multiple myeloma. In certain embodiments, the cancer is sarcoma. In certain embodiments, the sarcoma is Ewing’s sarcoma.
  • the histone demethylase is a KDM. In certain embodiments, the KDM is KDM5. In certain embodiments, the biological sample is a cell. In certain embodiments, the biological sample is a tissue.
  • kits described herein further includes instructions for using the compound or pharmaceutical composition included in the kit.
  • a kit described herein may also include information as required by a regulatory agency such as the U.S. Food and Drug
  • kits and instructions provide for treating a disease in a subject in need thereof, preventing a disease, such as a proliferative disease and / or cardiovascular disease in a subject in need thereof, inhibiting the activity of a histone demethylase in a subject, or biological sample.
  • a kit described herein may include one or more additional pharmaceutical agents described herein as a separate composition.
  • the histone demethylase is a KDM.
  • the KDM is KDM5.
  • the biological sample is a cell.
  • the biological sample is a tissue.
  • Example 1 ICsofor exemplary compounds.
  • IC50 inhibitory activity for KDM5 selective inhibitor PCK62 and other exemplary KDM5 inhibitors against KDM5B was determined in an alphascreen activity assay (FIG. 3; Table 1).
  • Exemplary KDM5 inhibitor PCK62 JADA62 was also screened against different KDMs (KDM5A, KDM5B, KDM5C; KDM3A, and KDM3B). (FIG. 3; Table 2).
  • PCK62 shows reasonable inhibitory activity of KDM5, as compared to other exemplary KDM5 inhibitors.
  • Ill Table 1 IC50 data for exemplary KDM5 inhibitors in a KDM5B alphascreen activity assay.
  • AlphaPlate Perkin Elmer, USA
  • transfer of pre-diiuted compound 100 nl was performed using a Janus Workstation (PerkinElmer, USA). All subsequent steps were carried out in assay buffer (50 mM HEPES, pH 7.5, 0.1% (wt/vol) BSA and 0.01% (vol/vol) Tween- 20).
  • assay buffer 50 mM HEPES, pH 7.5, 0.1% (wt/vol) BSA and 0.01% (vol/vol) Tween- 20.
  • the enzyme reaction was initiated by the addition of substrate (5 m ⁇ ) consisting of L-ascorbic acid (100 mM Final), 2-OG (5 uM Final), FAS (10 uM Final) and histone H3(l-21)K4Me3-GGK Biotin (lOOnM Final). The enzyme reaction was allowed to proceed for 30 minutes and was stopped by the addition of 5 m! of assay buffer containing EDTA (40 niM) and NaCl (1200 niM). The final concentration of DMSO was 1%.
  • Streptavidin donor beads (0.08 mg/ml) and protein-A-conjugated acceptor beads (0.08 mg/ml) were preincubated for 1 h with antibody to methyl mark (300 ng/ml Final), and the presence of histone H3 product methyl mark was detected using the preincubated AlphaScreen beads (5 m ⁇ ). Detection was allowed to proceed for 2 h at room temperature, and the assay plates were read on the Envision 2104 plate reader. Data were normalized to the (no-enzyme) control, and the IC50 values were determined via nonlinear regression curve fit using GraphPad Prism 7. The results of the Alphascreen assays are depicted in FIG. 3A-3B and FIG. 9A-9B.
  • Example 3 CTG assay for exemplary compounds.
  • Cell Titer g!o assays were performed by treating MM. IS cells with compounds at concentrations indicated. Anti-proliferative effects of compounds were assessed using Cell Titer Glo assay kit (Promega). IC50 values were determined using Graphpad Prism nonlinear regression curve fit.
  • the CellTiter-Glo® Luminescent Cell Viability Assay is a homogeneous method of determining the number of viable cells in culture based on quantitation of the ATP present, an indicator of meiaboiicaily active cells.
  • the CellTiter-Glo ⁇ Assay is designed for use with multiwell formats, making it ideal for automated high-throughput screening (HTS), cell proliferation and cytotoxicity assays.
  • the homogeneous assay procedure involves adding the single reagent (CellTiter-Glo® Reagent) directly to cells cultured in seru -supplemented medium. Cell washing, removal of medium and multiple pipetting steps are not required.
  • the system detects as few ' as 15 cells/well in a 384- well format in 10 minutes after adding reagent and mi ing.
  • the homogeneous“add-mix-measure” format results in cell lysis and generation of a luminescent signal proportional to the amount of ATP present.
  • the amount of ATP is directly proportional to the number of cells present in culture.
  • the CellTiter-Glo® Assay generates a "glow-type" luminescent signal, which has a half-life generally greater than five hours, depending on ceil type and medium used. The extended half-life eliminates the need to use reagent injectors and provides flexibility for continuous or batch mode processing of multiple plates.
  • the unique homogeneous format avoids errors that may be introduced by other ATP measurement methods that require multiple steps.
  • KDM5A inhibitor modestly induced apoptosis in MM cell lines after the cell cycle arrest, indicating that KDM5A is primarily required for MM cell proliferation rather than survival.
  • MYC deregulation of MYC is implicated in the pathogenesis of MM, and recent studies show that MYC selectively activates or represses its target genes, cooperating with other factors such as WDR5 and MIZ1 in a cancer- specific manner. Hence, the factors mediating cancer- specific MYC program could be ideal therapeutic targets in MYC-driven cancers.
  • pi JKQ.l -based plasmids for shRNAs were obtained from the RNAi Consortium (Broad Institute).
  • the RNAi Consortium clone ID and target sequence of each vector are provided in Table 4 below.
  • the human KDM5A and KDM5C cDNA was amplified using PCR and ligated into the Hpal and Xhol sites of pMSCV retroviral expression vector (Clontech).
  • Recombinant lentivirus was produced by transient transfection of 293T cells following a standard protocol. After 48 hours, MM cells were incubated with culture supernatants from 293T cells containing crude virus for 6 hours and washed with media. After 24h of infection, cells expressing shRNA were selected with puromycin dihydrochloride (Sigma- Aldrich) at 1-2 mg/ml for 48 h, and then examined for proliferation and/or subjected to immunoblotting analysis.
  • puromycin dihydrochloride Sigma- Aldrich
  • RNAi Consortium clone ID and target sequence of each vector was determined using the ModFit LT software (Verity Software House). Table 4. RNAi Consortium clone ID and target sequence of each vector.
  • the compounds provided herein can be prepared from readily available starting materials using the following general methods and procedures or methods known in the art. It will be appreciated that where typical process conditions (i.e ., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by those skilled in the art by routine optimization procedures.
  • mice were injected intravenously with luciferized molp8 cells. Half million cells per mice. After 1 week, the tumor was observed using bioluminescence imaging (BLI). The normalized total flux was measured over 17 days (FIG. 12; Table 5) Mice were randomized into control and treatment. Treatment lasted for 21 days. Animals with 15% weight loss was terminated.
  • the disclosure encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims is introduced into another claim.
  • any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim.
  • elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should it be understood that, in general, where the disclosure, or aspects described herein, is/are referred to as comprising particular elements and/or features, certain embodiments described herein or aspects described herein consist, or consist essentially of, such elements and/or features.

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